Input: Patients with the Denys-Drash syndrome (Wilms tumor, genital anomalies, and nephropathy) have been demonstrated to carry de novo constitutional mutations in WT1, the Wilms tumor gene at chromosome 11p13.

Denys-Drash syndrome

Wilms tumor

genital anomalies

nephropathy

Wilms tumor


Input: We report three new cases, two carrying a previously described WT1 exon 9 mutation and one with a novel WT1 exon 8 mutation.


Input: However, unlike patients in previous reports, one of our three patients inherited the affected allele from his phenotypically unaffected father.


Input: This observation indicates that the WT1 exon 9 mutation affecting 394Arg demonstrated in over one-half of the patients with the Denys-Drash syndrome may exhibit incomplete penetrance.

Denys-Drash syndrome


Input: Consequently, familial studies in patients affected by this syndrome are recommended..


Input: Submicroscopic deletions at the WAGR locus, revealed by nonradioactive in situ hybridization.

WAGR


Input: Fluorescence in situ hybridization (FISH) with biotin-labeled probes mapping to 11p13 has been used for the molecular analysis of deletions of the WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) locus.

WAGR

Wilms tumor

aniridia

genitourinary abnormalities

mental retardation


Input: We have detected a submicroscopic 11p13 deletion in a child with inherited aniridia who subsequently presented with Wilms tumor in a horseshoe kidney, only revealed at surgery.

aniridia

Wilms tumor


Input: The mother, who has aniridia, was also found to carry a deletion including both the aniridia candidate gene (AN2) and the Wilms tumor predisposition gene (WT1).

aniridia

aniridia

Wilms tumor


Input: This is therefore a rare case of an inherited WAGR deletion.

WAGR


Input: Wilms tumor has so far only been associated with sporadic de novo aniridia cases.

Wilms tumor

aniridia


Input: We have shown that a cosmid probe for a candidate aniridia gene, homologous to the mouse Pax-6 gene, is deleted in cell lines from aniridia patients with previously characterized deletions at 11p13, while another cosmid marker mapping between two aniridia-associated translocation breakpoints (and hence a second candidate marker) is present on both chromosomes.

aniridia

aniridia

aniridia


Input: These results support the Pax-6 homologue as a strong candidate for the AN2 gene.


Input: FISH with cosmid probes has proved to be a fast and reliable technique for the molecular analysis of deletions.


Input: It can be used with limited amounts of material and has strong potential for clinical applications..


Input: Linkage of gene for C2 deficiency and the major histocompatibility complex MHC in man.

C2 deficiency


Input: Family study of a further case.


Input: Close linkage between HL-A and C2 deficiency was first reported by FU and co-workers in 1974.

C2 deficiency


Input: We present here a pedigree of a 31-year-old C2-deficient individual with clinical manifestations of Hodgkins disease.

Hodgkins disease


Input: The following markers were tested C2 levels, factor B polymorphism, blood groups, and enzyme typing.


Input: In addition to close linkage between HL-A and C2 deficiency, both parents were heterozygous for Bf (HL-A linked, electrophoretic variation of B).

C2 deficiency


Input: The two HL-A haplotypes closely linked to C2 deficiency are different 2, W18 and W24, W18.

C2 deficiency


Input: They share, however, the SD2 antigen W18 and the LD type 7a..


Input: Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients.

familial adenomatous polyposis


Input: We report here the result of a screening for germ-line mutations in the adenomatous polyposis coli (APC) gene in 61 new familial adenomatous polyposis (FAP) patients as well as a summary of the results of 150 patients.

adenomatous polyposis coli

APC

familial adenomatous polyposis

FAP


Input: Examination of the entire coding region of the APC gene, based on a ribonuclease protection assay coupled with the polymerase chain reaction (PCR), disclosed mutations that were considered to cause significant defects in the APC product in 97 of 150 unrelated FAP patients.

APC

APC

FAP


Input: Our findings revealed the following characteristics of the germ-line mutations of APC 1) the great majority of the mutations were found to truncate the APC product; 2) almost all of the mutations were located within the first half of the coding region; 3) no correlation was observed between the locations of germ-line mutations and extracolonic manifestations in FAP patients; 4) more than 80% of base substitutions in the APC gene were from cytosine to other nucleotides, nearly one-third of which occurred at the GpG site.

APC

FAP

APC


Input: Our results provide information helpful to an understanding of the APC gene and will also contribute to presymptomatic diagnosis of members in FAP families..

APC

FAP


Input: Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene.

APC

colorectal tumors

APC


Input: We examined somatic mutations of the adenomatous polyposis coli (APC) gene in 63 colorectal tumors (16 adenomas and 47 carcinomas) developed in familial adenomatous polyposis (FAP) and non-FAP patients.

adenomatous polyposis coli

APC

colorectal tumors

adenomas

carcinomas

familial adenomatous polyposis

FAP


Input: In addition to loss of heterozygosity (LOH) at the APC locus in 30 tumors, 43 other somatic mutations were detected.

APC

tumors


Input: Twenty-one of them were point mutations; 16 nonsense and two missense mutations, and three occurred in introns at the splicing site.


Input: Twenty-two tumors had frameshift mutations due to deletion or insertion; nineteen of them were deletions of one to 31 bp and three were a 1-bp insertion.

tumors


Input: One tumor had a 1-bp deletion in an intron near the splicing site.

tumor


Input: Hence, 41 (95%) of 43 mutations resulted in truncation of the APC protein.

APC


Input: Over 60% of the somatic mutations in the APC gene were clustered within a small region of exon 15, designated as MCR (mutation cluster region), which accounted for less than 10% of the coding region.

APC


Input: Combining these data and the results of LOH, more than 80% of tumors (14 adenomas and 39 carcinomas) had at least one mutation in the APC gene, of which more than 60% (9 adenomas and 23 carcinomas) had two mutations.

tumors

adenomas

carcinomas

APC

adenomas

carcinomas


Input: These results strongly suggest that somatic mutations of the APC gene are associated with development of a great majority of colorectal tumors..

APC

colorectal tumors


Input: Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome.

Denys-Drash syndrome


Input: The Denys-Drash syndrome is characterised by a typical nephropathy, genital abnormalities and also predisposes to the development of Wilms tumor.

Denys-Drash syndrome

nephropathy

genital abnormalities

Wilms tumor


Input: These patients eventually go into end stage renal failure.

renal failure


Input: A candidate Wilms tumor gene, WT1, from the 11p13 chromosome region has recently been cloned.

Wilms tumor


Input: We have analysed the DNA sequence in constitutional cells from eight patients and have shown heterozygous mutations in six of them.


Input: Four of the mutations were in exon 9, all resulting in missense mutations.


Input: Three were at nucleotide position 1180 resulting in an arg > trp amino acid change.


Input: The other was at position 1186 converting an asp > asn in the predicted resultant protein.


Input: One patient had a missense mutation in exon 8, converting an arg > his.


Input: A single base pair insertion at nucleotide position 821 in exon 6 resulted in the generation of a premature stop codon in the last patient.


Input: We were unable to find a mutation in one patient despite complete sequencing of the genomic sequence of the gene.


Input: The last patient carried a constitutional deletion of the 11p13 region and no additional mutation was found.


Input: There was no obvious correlation between the type of mutation and phenotypic expression.


Input: These results further demonstrate that the WT1 gene is important in both the development of the kidney and the genito-urinary system..


Input: Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland.

diastrophic dysplasia


Input: Linkage disequilibrium mapping in isolated populations provides a powerful tool for fine structure localization of disease genes.


Input: Here, Luria and Delbrucks classical methods for analysing bacterial cultures are adapted to the study of human isolated founder populations in order to estimate (i) the recombination fraction between a disease locus and a marker; (ii) the expected degree of allelic homogeneity in a population; and (iii) the mutation rate of marker loci.


Input: Using these methods, we report striking linkage disequilibrium for diastrophic dysplasia (DTD) in Finland indicating that the DTD gene should lie within 0.

diastrophic dysplasia

DTD

DTD


Input: 06 centimorgans (or about 60 kilobases) of the CSF1R gene.


Input: Predictions about allelic homogeneity in Finland and mutation rates in simple sequence repeats are confirmed by independent observations.


Input: The Wiskott-Aldrich syndrome: refinement of the localization on Xp and identification of another closely linked marker locus, OATL1.

Wiskott-Aldrich syndrome


Input: The Wiskott-Aldrich syndrome (WAS) has previously been mapped to the proximal short arm of the X chromosome between the DXS14 and DXS7 loci.

Wiskott-Aldrich syndrome

WAS


Input: In this study, further segregation analysis has been performed using a newly identified WAS family as well as an additional marker probe, HOATL1.

WAS


Input: The results indicate close linkage between the WAS and OATL1 loci (Z = 6. 08 at theta = 0. 00) and localize the TIMP, OATL1, DXS255, and WAS loci distal to DXS146 and the OATL1 and WAS loci proximal to TIMP.

WAS

WAS

WAS


Input: These linkage data narrow the boundaries within which the WAS locus maps to the chromosomal region bracketed by TIMP and DXS146 and support the loci order Xpter-DXS7-TIMP-(OATL1, WAS, DXS255)-DXS146.

WAS


Input: Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy.

myotonic dystrophy


Input: Myotonic dystrophy (DM) is the most common form of adult muscular dystrophy, with a prevalence of 2-14 per 100, 000 individuals.

Myotonic dystrophy

DM

muscular dystrophy


Input: The disease is characterized by progressive muscle weakness and sustained muscle contraction, often with a wide range of accompanying symptoms.

muscle weakness

sustained muscle contraction


Input: The age at onset and severity of the disease show extreme variation, both within and between families.


Input: Despite its clinical variability, this dominant condition segregates as a single locus at chromosome 19q13.


Input: 3 in every population studied.


Input: It is flanked by the tightly linked genetic markers ERCC1 proximally and D19S51 distally; these define the DM critical region.

DM


Input: We report the isolation of an expressed sequence from this region which detects a DNA fragment that is larger in affected individuals than in normal siblings or unaffected controls.


Input: The size of this fragment varies between affected siblings, and increases in size through generations in parallel with increasing severity of the disease.


Input: We postulate that this unstable DNA sequence is the molecular feature that underlies DM.

DM


Input: Common sequence motifs at the rearrangement sites of a constitutional X/autosome translocation and associated deletion.


Input: Reciprocal chromosome translocations are common de novo rearrangements that occur randomly throughout the human genome.


Input: To learn about causative mechanisms, we have cloned and sequenced the breakpoints of a cytologically balanced constitutional reciprocal translocation, t (X; 4) (p21. 2; q31. 22), present in a girl with Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy

DMD


Input: Physical mapping of the derivative chromosomes, after their separation in somatic cell hybrids, reveals that the translocation disrupts the DMD gene in Xp21 within the 18-kb intron 16.

DMD


Input: Restriction mapping and sequencing of clones that span both translocation breakpoints as well as the corresponding normal regions indicate the loss of approximately 5 kb in the formation of the derivative X chromosome, with 4-6 bp deleted from chromosome 4.


Input: RFLP and Southern analyses indicate that the de novo translocation is a paternal origin and that the fathers X chromosome contains the DNA that is deleted in the derivative X.


Input: Most likely, deletion and translation arose simultaneously from a complex rearrangement event that involves three chromosomal breakpoints.


Input: Short regions of sequence homology were present at the three sites.


Input: A 5-bp sequence, GGAAT, found exactly at the translocation breakpoints on both normal chromosomes X and 4, has been preserved only on the der (4) chromosome.


Input: It is likely that the X-derived sequence GGAATCA has been lost in the formation of the der (X) chromosome, as it matches an inverted GAATCA sequence present on the opposite strand exactly at the other end of the deleted 5-kb fragment.


Input: A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11.

DiGeorge syndrome


Input: DiGeorge syndrome (DGS), a developmental field defect of the third and fourth pharyngeal pouches, is characterized by aplasia or hypoplasia of the thymus and parathyroid glands and by conotruncal cardiac malformations.

DiGeorge syndrome

DGS

aplasia or hypoplasia of the thymus and parathyroid glands

conotruncal cardiac malformations


Input: Cytogenetic studies support the presence of a DGS critical region in band 22q11.

DGS


Input: In the present study, we report the results of clinical, cytogenetic, and molecular studies of 14 patients with DGS.

DGS


Input: Chromosome analysis, utilizing high-resolution banding techniques, detected interstitial deletions in five probands and was inconclusive for a deletion in three probands.


Input: The remaining six patients had normal karyotypes.


Input: In contrast, molecular analysis detected DNA deletions in all 14 probands.


Input: Two of 10 loci tested, D22S75 and D22S259, are deleted in all 14 patients.


Input: A third locus, D22S66, is deleted in the eight DGS probands tested.

DGS


Input: Physical mapping using somatic cell hybrids places D22S66 between D22S75 and D22S259, suggesting that it should be deleted in the remaining six cases.


Input: Parent-of-origin studies were performed in five families.


Input: Four probands failed to inherit a maternal allele, and one failed to inherit a paternal allele.


Input: On the basis of these families, and of six maternally and five paternally derived unbalanced-translocation DGS probands in the literature, parent of origin or imprinting does not appear to play an important role in the pathogenesis of DGS.

DGS

DGS


Input: Deletion of the same three loci in all 14 DGS probands begins to delineate the region of chromosome 22 critical for DGS and confirms the hypothesis that submicroscopic deletions of 22q11 are etiologic in the vast majority of cases..

DGS

DGS


Input: Loss of normal allele of the APC gene in an adrenocortical carcinoma from a patient with familial adenomatous polyposis.

APC

adrenocortical carcinoma

familial adenomatous polyposis


Input: Endocrine neoplasms have been reported occasionally in patients with familial adenomatous polyposis (FAP).

Endocrine neoplasms

familial adenomatous polyposis

FAP


Input: An adrenocorotical carcinoma was studied in a patient with a family history of FAP.

adrenocorotical carcinoma

FAP


Input: Loss of heterozygosity (LOH) in the region close to the adenomatous polyposis coli (APC) gene was detected in this carcinoma, and evidence was obtained that there was a loss of the normal allele of the APC gene.

adenomatous polyposis coli

APC

carcinoma

APC


Input: This is the first demonstration of LOH at the APC locus in adrenocortical tumors.

APC

adrenocortical tumors


Input: The present results and our previous data on LOH in a recurring desmoid tumor suggest that the heterozygous mutant/wild-type condition of the APC gene may give rise to benign tumors, and that functional loss of this gene leads to development of tumors not only in the colon but also in other various parts of the body in FAP patients..

desmoid tumor

APC

benign tumors

tumors

FAP


Input: Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype.

retinoblastoma


Input: The retinoblastoma-predisposition gene, RB1, segregates as an autosomal dominant trait with high (90%) penetrance.

retinoblastoma


Input: Certain families, however, show an unusual low-penetrance phenotype with many individuals being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors.

tumors


Input: We have used single-strand conformation polymorphism analysis and PCR sequencing to study two such families.


Input: Mutations were found in exon 20 of RB1 in both cases.


Input: In one family a C----T transition in codon 661 converts an arginine (CGG) to a tryptophan (TGG) codon.


Input: In this family, incomplete penetrance and mild phenotypic expression were observed in virtually all patients, possibly indicating that single amino acid changes may modify protein structure/function such that tumorigenesis is not inevitable.


Input: In the second family the mutation in codon 675 is a G----T transversion that converts a glutamine (GAA) to a stop (TAA) codon.


Input: However, this mutation also occurs near a potential cryptic splice acceptor site, raising the possibility of alternative splicing resulting in a less severely disrupted protein..


Input: Late-onset metachromatic leukodystrophy: molecular pathology in two siblings.

metachromatic leukodystrophy


Input: We report on a new allele at the arylsulfatase A (ARSA) locus causing late-onset metachromatic leukodystrophy (MLD).

metachromatic leukodystrophy

MLD


Input: In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine.


Input: In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity.

MLD


Input: A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD..

MLD

MLD


Input: Trisomy 15 with loss of the paternal 15 as a cause of Prader-Willi syndrome due to maternal disomy.

Trisomy 15

Prader-Willi syndrome

maternal disomy


Input: Uniparental disomy has recently been recognized to cause human disorders, including Prader-Willi syndrome (PWS).

Uniparental disomy

Prader-Willi syndrome

PWS


Input: We describe a particularly instructive case which raises important issues concerning the mechanisms producing uniparental disomy and whose evaluation provides evidence that trisomy may precede uniparental disomy in a fetus.

uniparental disomy

uniparental disomy


Input: Chorionic villus sampling performed for advanced maternal age revealed trisomy 15 in all direct and cultured cells, though the fetus appeared normal.

trisomy 15


Input: Chromosome analysis of amniocytes obtained at 15 wk was normal in over 100 cells studied.


Input: The child was hypotonic at birth, and high-resolution banding failed to reveal the deletion of 15q11-13, a deletion which is found in 50%-70% of patients with PWS.

hypotonic

PWS


Input: Over time, typical features of PWS developed.

PWS


Input: Molecular genetic analysis using probes for chromosome 15 revealed maternal disomy.


Input: Maternal nondisjunction with fertilization of a disomic egg by a normal sperm, followed by loss of the paternal 15, is a likely cause of confined placental mosaicism and uniparental disomy in this case of PWS, and advanced maternal age may be a predisposing factor..

uniparental disomy

PWS


Input: Genetic heterogeneity in X-linked amelogenesis imperfecta.

X-linked amelogenesis imperfecta


Input: The AMELX gene located at Xp22.


Input: 3 encodes for the enamel protein amelogenin and has been implicated as the gene responsible for the inherited dental abnormality X-linked amelogenesis imperfecta (XAI).

inherited dental abnormality X-linked amelogenesis imperfecta

XAI


Input: Three families with XAI have been investigated using polymorphic DNA markers flanking the position of AMELX.

XAI


Input: Using two-point linkage analysis, linkage was established between XAI and several of these markers in two families, with a combined lod score of 6.

XAI


Input: 05 for DXS16 at theta = 0.


Input: 04 04.


Input: This supports the involvement of AMELX, located close to DXS16, in the XAI disease process (AIH1) in those families.

XAI disease


Input: Using multipoint linkage analysis, the combined maximum lod score for these two families was 7.


Input: 30 for a location of AIH1 at 2 cM distal to DXS16.


Input: The support interval around this location extended about 8 cM proximal to DXS92, and the AIH1 location could not be precisely defined by multipoint mapping.


Input: Study of recombination events indicated that AIH1 lies in the interval between DXS143 and DXS85.


Input: There was significant evidence against linkage to this region in the third family, indicating locus heterogeneity in XAI.

XAI


Input: Further analysis with markers on the long arm of the X chromosome showed evidence of linkage to DXS144E and F9 with no recombination with either of these markers.


Input: Two-point analysis gave a peak lod score at DXS144E with a maximum lod score of 2.


Input: 83 at theta = 0, with a peak lod score in multipoint linkage analysis of 2.


Input: 84 at theta = 0.


Input: The support interval extended 9 cM proximal to DXS144E and 14 cM distal to F9.


Input: (ABSTRACT TRUNCATED AT 250 WORDS).


Input: Multiple origins for phenylketonuria in Europe.

phenylketonuria


Input: Phenylketonuria (PKU), a disorder of amino acid metabolism prevalent among Caucasians and other ethnic groups, is caused primarily by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH).

Phenylketonuria

PKU

disorder of amino acid metabolism

deficiency of the hepatic enzyme phenylalanine hydroxylase


Input: PKU is a highly heterogeneous disorder, with more than 60 molecular lesions identified in the PAH gene.

PKU


Input: The haplotype associations, relative frequencies, and distributions of five prevalent PAH mutations (R158Q, R261Q, IVS10nt546, R408W, and IVS12n1) were established in a comprehensive European sample population and subsequently were examined to determine the potential roles of several genetic mechanisms in explaining the present distribution of the major PKU alleles.

PKU


Input: Each of these five mutations was strongly associated with only one of the more than 70 chromosomal haplotypes defined by eight RFLPs in or near the PAH gene.


Input: These findings suggest that each of these mutations arose through a single founding event that occurred within time periods ranging from several hundred to several thousand years ago.


Input: From the significant differences observed in the relative frequencies and distributions of these five alleles throughout Europe, four of these putative founding events could be localized to specific ethnic subgroups.


Input: Together, these data suggest that there were multiple, geographically and ethnically distinct origins for PKU within the European population..

PKU


Input: Complement factor 2 deficiency: a clinical and serological family study.

Complement factor 2 deficiency


Input: Inherited complement deficiencies are associated with a variety of connective tissue diseases.

Inherited complement deficiencies


Input: A family with inherited deficiency of complement factor 2 (C2) is described in which two family members with homozygous C2 deficiency developed cutaneous vasculitis and sicca syndrome.

inherited deficiency of complement factor 2

C2 deficiency

cutaneous vasculitis

sicca syndrome


Input: The other family members had heterozygous C2 deficiency and each member had the HLA-A25, B18, DR2 (w15) haplotype.

C2 deficiency


Input: The mother had seropositive rheumatoid arthritis.

seropositive rheumatoid arthritis


Input: Further studies showed the presence of cryoglobulins, antibodies against endothelial cells, and anticardiolipin antibodies..


Input: New variant in exon 3 of the proteolipid protein (PLP) gene in a family with Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease


Input: A C--greater than G transversion has been found in exon 3 of the PLP gene of affected males and their mother in a single sibship with Pelizaeus-merzbacher disease (PMD).

Pelizaeus-merzbacher disease

PMD


Input: The transversion should not result in an amino acid change in the protein but it does result in the loss of a HaeIII restriction endonuclease cleavage site.


Input: It is concordant with the disease in this family.


Input: One-hundred-ten unrelated X chromosomes are negative for this mutation.


Input: No other sequence defect was found in the PLP exons of the affected males.


Input: The cause of disease in this family remains unknown, but the association between this rare mutation and PMD is intriguing.

PMD


Input: The mutation can serve as a marker for following segregation of the PLP gene..


Input: Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.

hypomyelination

glial cell death


Input: Proteolipid protein (PLP; M (r) 30, 000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure.


Input: Neurological mutant mice can often provide model systems for human genetic disorders.

genetic disorders


Input: Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse and subsequently in patients with Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease


Input: The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination.

degeneration and premature cell death of oligodendrocytes

hypomyelination


Input: Here we show that a new mouse mutant rumpshaker is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP.


Input: Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes.

myelin-deficient


Input: Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration.

Hypomyelination

oligodendrocyte degeneration


Input: We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease..

Pelizaeus-Merzbacher disease


Input: A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.

Tay-Sachs


Input: Deficiency of beta-hexosaminidase A (Hex A) activity typically results in Tay-Sachs disease.

Deficiency of beta-hexosaminidase A

Tay-Sachs disease


Input: However, healthy subjects found to be deficient in Hex A activity (i. e., pseudodeficient) by means of in vitro biochemical tests have been described.

deficient in Hex A


Input: We analyzed the HEXA gene of one pseudodeficient subject and identified both a C739-to-T substitution that changes Arg247----Trp on one allele and a previously identified Tay-Sachs disease mutation on the second allele.

Tay-Sachs disease


Input: Six additional pseudodeficient subjects were found to have the C739-to-T mutation.


Input: This allele accounted for 32% (20/62) of non-Jewish enzyme-defined Tay-Sachs disease carriers but for none of 36 Jewish enzyme-defined carriers who did not have one of three known mutations common to this group.

Tay-Sachs disease


Input: The C739-to-T allele, together with a " true " Tay-Sachs disease allele, causes Hex A pseudodeficiency.

Tay-Sachs disease


Input: Given both the large proportion of non-Jewish carriers with this allele and that standard biochemical screening cannot differentiate between heterozygotes for the C739-to-T mutations and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential.

Tay-Sachs disease


Input: Pelizaeus-Merzbacher disease: detection of mutations Thr181----Pro and Leu223----Pro in the proteolipid protein gene, and prenatal diagnosis.

Pelizaeus-Merzbacher disease


Input: A family with an apparent history of X-linked Pelizaeus-Merzbacher disease presented for genetic counseling, requesting carrier detection and prenatal diagnosis.

Pelizaeus-Merzbacher disease


Input: RFLP analysis using the proteolipid protein (PLP) gene probe was uninformative in this family.


Input: A prenatal diagnosis on a chorionic villus sample (CVS) was carried out using single-strand conformation polymorphism (SSCP) analysis of a variant in exon 4 of the PLP gene.


Input: The fetus was predicted to be unaffected.


Input: Sequencing of the exon from the CVS, the predicted-carrier mother, and the obligate-carrier grandmother revealed an A-to-C change at nucleotide 541 in the two women but not in the fetus.


Input: As this change results in a Thr-to-Pro change at amino acid 181 in a region of the gene predicted to be part of a transmembrane segment, it was concluded that this was the mutation causing the disease in this family.


Input: In addition, in a second family, an exon 5 variant band pattern on SSCP analysis was shown by sequencing to be due to a T-to-C change at nucleotide 668.


Input: This results in a Leu-to-Pro change in a carrier mother and in her two affected sons.


Input: These results provide further examples of mutations in PLP that cause Pelizaeus-Merzbacher disease and illustrate the value of SSCP in genetic analysis..

Pelizaeus-Merzbacher disease


Input: von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib.

von Willebrand disease type B

von Willebrand


Input: von Willebrand factor (vWF) is a multimeric glycoprotein that mediates the adhesion of platelets to the subendothelium by binding to platelet glycoprotein Ib.

von Willebrand


Input: For human vWF, this interaction can be induced in vitro by the antibiotic ristocetin or the snake venom protein botrocetin.


Input: A missense mutation, Gly-561--> Ser, was identified within the proposed glycoprotein Ib binding domain of vWF in the proband with von Willebrand disease type B, a unique variant characterized by no ristocetin-induced, but normal botrocetin-induced, binding to glycoprotein Ib.

von Willebrand disease type B


Input: The corresponding mutant recombinant protein, rvWF (G561S), formed normal multimers and exhibited the same functional defect as the patients plasma vWF, confirming that this mutation causes von Willebrand disease type B.

von Willebrand disease type B


Input: These data show that botrocetin and ristocetin cofactor activities of vWF can be dissociated by a point mutation and confirm that these mediators promote vWF binding to platelets by different mechanisms.


Input: The normal botrocetin-induced binding and the defective ristocetin-induced binding of rvWF (G561S) suggest that the primary defect in von Willebrand disease type B may be a failure of normal allosteric regulation of the glycoprotein Ib binding function of vWF..

von Willebrand disease type B


Input: Typical and partial cat eye syndrome: identification of the marker chromosome by FISH.

cat eye syndrome


Input: Three children are reported with typical cat eye syndrome (CES) and three more children with partial CES because of absence of coloboma, in which the supernumerary marker chromosome was studied by FISH.

cat eye syndrome

CES

CES


Input: Using a genomic library, and also a centromeric and particularly a cosmid probe of 22q11, partial tetrasomy was shown in all cases..

tetrasomy


Input: [Genetic heterogeneity of G6PD deficiency: mutant alleles of G6PD in the Shekii district of Azerbaijan]

G6PD deficiency


Input: Examination on G6PD deficiency in 349 patients of Shekii district hospital (Azerbaijan) revealed 16 hemi-, 4 homo-and 9 heterozygotic carriers of the defect.

G6PD deficiency


Input: Gd-frequency, calculated from the data obtained (7. 7%), may be compared to neighbouring regions frequencies (6-30%).


Input: Carriers of G6PD deficiency are residents of 11 villages located in Alasani-Aphtalan valley, highly endemic with malaria in the past; nearly all marriages are endogamic.

G6PD deficiency

malaria


Input: Physico-chemical and kinetic study of 10 mutant forms of G6PD, according to WHO program, led to identification of 5 variants of the II class (Shekii, Bideiz, Shirin-Bulakh, Okhut I and Zakataly) and 2 variants of the III class (Okhut II and Martinique-like).


Input: Resemblance of the majority of variants in electrophoretic mobility and the level of erythrocyte enzyme activity permit to suggest the existence of a common parental mutant G6PD allele distributed in this area.


Input: Craniofrontonasal dysplasia.

Craniofrontonasal dysplasia


Input: We report on nine patients with craniofrontonasal dysplasia (CFND).

craniofrontonasal dysplasia

CFND


Input: Seven classical cases had facial features suggestive of frontonasal dysplasia and coronal craniosynostosis.

frontonasal dysplasia

coronal craniosynostosis


Input: Extracranial abnormalities such as brittle nails with prominent longitudinal grooves or syndactyly of fingers and toes were observed in individual patients.

Extracranial abnormalities

brittle nails with prominent longitudinal grooves

syndactyly of fingers and toes


Input: In two families the father of classical cases showed a milder pattern of abnormalities, consistent with the diagnosis.


Input: We present a 2-to 13-year follow-up on our patients.


Input: Hypotonia and laxity of joints are common and may necessitate supportive measures.

Hypotonia

laxity of joints


Input: Mild developmental delay was noted in three out of six classical cases studied in detail.

developmental delay


Input: Unlike almost all other X-linked disorders, clinical expression in CFND is generally much more severe in females than in males.

X-linked disorders

CFND


Input: In contrast to previous reports of this condition, one of our severely affected cases is a male..


Input: The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada.

Tay-Sachs disease


Input: Mutations at the hexosaminidase A (HEXA) gene which cause Tay-Sachs disease (TSD) have elevated frequency in the Ashkenazi Jewish and French-Canadian populations.

Tay-Sachs disease

TSD


Input: We report a novel TSD allele in the French-Canadian population associated with the infantile form of the disease.

TSD


Input: The mutation, a G--> A transition at the + 1 position of intron 7, abolishes the donor splice site.


Input: Cultured human fibroblasts from a compound heterozygote for this transition (and for a deletion mutation) produce no detectable HEXA mRNA.


Input: The intron 7 + 1 mutation occurs in the base adjacent to the site of the adult-onset TSD mutation (G805A).

TSD


Input: In both mutations a restriction site for the endonuclease EcoRII is abolished.


Input: Unambiguous diagnosis, therefore, requires allele-specific oligonucleotide hybridization to distinguish between these two mutant alleles.


Input: The intron 7 + 1 mutation has been detected in three unrelated families.


Input: Obligate heterozygotes for the intron 7 + 1 mutation were born in the Saguenay-Lac-St-Jean region of Quebec.


Input: The most recent ancestors common to obligate carriers of this mutation were from the Charlevoix region of the province of Quebec.


Input: This mutation thus has a different geographic centre of diffusion and is probably less common than the exon 1 deletion TSD mutation in French Canadians.

TSD


Input: Neither mutation has been detected in France, the ancestral homeland of French Canada..


Input: Assignment of the aspartylglucosaminidase gene (AGA) to 4q33----q35 based on decreased activity in a girl with a 46, XX, del (4) (q33) karyotype.


Input: Aspartylglucosaminuria (AGU) is a recessive autosomally inherited lysosomal storage disorder due to deficiency of the enzyme aspartylglucosaminidase (AGA).

Aspartylglucosaminuria

AGU

lysosomal storage disorder

deficiency of the enzyme aspartylglucosaminidase


Input: The structural gene for this human enzyme (AGA) has been assigned to the region 4q21----qter.


Input: We determined the AGA activity in cultured fibroblasts of a girl with a 46, XX, del (4) (q33) karyotype.


Input: The results indicate that the girl is a hemizygote for AGA, permitting the assignment of human AGA to the region 4q33----qter..


Input: Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome 11p13.

aniridia


Input: Two distinct loci have been proposed for aniridia; AN1 for autosomal dominant aniridia on chromosome 2p and AN2 for the aniridia in the WAGR contiguous gene syndrome on chromosome 11p13.

aniridia

aniridia

aniridia

WAGR contiguous gene syndrome


Input: In this report, the kindred segregating for autosomal dominant aniridia, which suggested linkage to acid phosphatase-1 (ACP1) and led to the assignment of the AN1 locus on chromosome 2p, has been updated and expanded.

aniridia


Input: Linkage analysis between the aniridia phenotype and ACP1 does not support the original linkage results, excluding linkage up to theta = 0.

aniridia


Input: 17 with Z =-2.


Input: Tests for linkage to other chromosome 2p markers.


Input: APOB, D2S71, D2S5, and D2S1, also excluded linkage to aniridia.

aniridia


Input: Markers that have been isolated from the chromosome 11p13 region were then analyzed in this aniridia family.

aniridia


Input: Two RFLPs at the D11S323 locus give significant evidence for linkage.


Input: The PvuII polymorphism detected by probe p5S1.


Input: 6 detects no recombinants, with a maximum lod score of Z = 6.


Input: 97 at theta = 0.


Input: 00 00.


Input: The HaeIII polymorphism detected by the probe p5BE1.


Input: 2 gives a maximum lod score of Z = 2.


Input: 57 at theta = 0.


Input: 00 00.


Input: Locus D11S325 gives a lod score of Z = 1.


Input: 53 at theta = 0.


Input: 00 00.


Input: These data suggest that a locus for aniridia (AN1) on chromosome 2p has been misassigned and that this autosomal dominant aniridia family is segregating for an aniridia mutation linked to markers in the 11p13 region.

aniridia

aniridia

aniridia


Input: Fatal pyoderma gangrenosum in association with C7 deficiency.

pyoderma gangrenosum

C7 deficiency


Input: Although pyoderma gangrenosum (PG) is often associated with systemic diseases, it has not been reported in association with congenital complement deficiencies.

pyoderma gangrenosum

PG

systemic diseases

congenital complement deficiencies


Input: We describe an aggressive and ultimately fatal case of PG in a patient with a congenital C7 deficiency.

PG

C7 deficiency


Input: Deficiencies of C7 can be associated with decreased neutrophil chemotaxis, phagocytosis, and opsonization, similar to the immunologic abnormalities described in patients with PG.

Deficiencies of C7

immunologic abnormalities

PG


Input: Our patients decreased complement level, if not directly related to the development of PG, may have contributed to the aggressive nature of her disease..

PG


Input: Diverse point mutations result in glucose-6-phosphate dehydrogenase (G6PD) polymorphism in Taiwan.


Input: Glucose-6-PHOSPHATE dehydrogenase (G6PD; EC 1. 1. 1. 49) deficiency is the most common human enzymopathy, affecting more than 200 million people worldwide.

Glucose-6-PHOSPHATE dehydrogenase (G6PD; EC 1. 1. 1. 49) deficiency

enzymopathy


Input: Although greater than 400 variants have been described based on clinical and biochemical criteria, little is known about the molecular basis of these G6PD deficiencies.

G6PD deficiencies


Input: Recently, the gene that encodes human G6PD has been cloned and sequenced, which enables us to examine directly the heterogeneity of G6PD at the DNA level.


Input: During the past 10 years, we examined the G6PD activity in 21, 271 newborn Chinese infants (11, 400 males and 9, 871 females) and identified 314 (2. 8%) males and 246 (2. 5%) females having low G6PD activity.


Input: The G6PD gene from 10 randomly selected affected individuals and their relatives was polymerase chain reaction (PCR) amplified, subcloned, and sequenced.


Input: Our results indicate that at least four types of mutation are responsible for the G6PD polymorphism in Taiwan.


Input: The first type of mutation (487 G----A) was found in an affected Chinese with a G to A change at nucleotide 487, which results in a (163) Gly to Ser substitution.


Input: The second type of mutation (493 A----G) is a novel mutation that has not been reported in any other ethnic group and was identified in two affected Chinese.


Input: This mutation causes an A to G change at nucleotide position 493, producing an (165) Asn to Asp substitution.


Input: Interestingly, the 487 G----A and 493 A----G mutations create Alu I and Ava II recognition sites, respectively, which enabled us to rapidly detect these two mutations by PCR/restriction enzyme (RE) digestion method.


Input: The third mutation (1376 G----T) was found in four affected Chinese.


Input: This mutation causes a G to T change at nucleotide position 1376 that results in an (459) Arg to Leu substitution.


Input: The 1376 G----T mutation seems to be the dominant allele that causes G6PD deficiency in Taiwan.

G6PD deficiency


Input: Finally, two affected Chinese were identified as having the fourth mutation (1388 G----A).


Input: This mutation causes a G to A change at nucleotide 1388 that produces an (463) Arg to His substitution.


Input: Our studies provide the direct proof of the genetic heterogeneity of G6PD deficiency in the Chinese populations of Taiwan and the PCR/RE digestion method is suitable for simultaneous detection of the 487 G----A and 493 A----G mutations.

G6PD deficiency


Input: An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy.

golden retriever muscular dystrophy

Duchenne muscular dystrophy


Input: Golden retriever muscular dystrophy (GRMD) is a spontaneous, X-linked, progressively fatal disease of dogs and is also a homologue of Duchenne muscular dystrophy (DMD).

Golden retriever muscular dystrophy

GRMD

Duchenne muscular dystrophy

DMD


Input: Two-thirds of DMD patients carry detectable deletions in their dystrophin gene.

DMD


Input: The defect underlying the remaining one-third of DMD patients is undetermined.

DMD


Input: Analysis of the canine dystrophin gene in normal and GRMD dogs has failed to demonstrate any detectable loss of exons.

GRMD


Input: Here, we have demonstrated a RNA processing error in GRMD that results from a single base change in the 3 consensus splice site of intron 6.

GRMD


Input: The seventh exon is then skipped, which predicts a termination of the dystrophin reading frame within its N-terminal domain in exon 8.


Input: This is the first example of dystrophin deficiency caused by a splice-site mutation..

dystrophin deficiency


Input: Type I human complement C2 deficiency.

Type I human complement C2 deficiency


Input: A 28-base pair gene deletion causes skipping of exon 6 during RNA splicing.


Input: Two variants of a genetic deficiency of complement protein C2 (C2D) have been previously identified.

deficiency of complement protein C2


Input: No C2 protein translation is detected in type I deficiency, while type II deficiency is characterized by a selective block in C2 secretion.


Input: Type I C2 deficiency was described in a family in which the C2 null allele (C2Q0) is associated with the major histocompatibility haplotype/complotype HLA-A25, B18, C2Q0, BfS, C4A4, C4B2, Drw2; this extended haplotype occurs in over 90% of C2-deficient individuals (common complotype/haplotype).

Type I C2 deficiency


Input: To determine the molecular basis of type I C2 deficiency, the C2 gene and cDNA were characterized from a homozygous type I C2-deficient individual with the common associated haplotype/complotype.

type I C2 deficiency

type I C2-deficient


Input: We found a 28-base pair deletion in the type I C2Q0 gene, beginning 9 base pairs upstream of the 3-end of exon 6, that generates a C2 transcript with a complete deletion of exon 6 (134 base pair) and a premature termination codon.


Input: In studies of eight kindred, the 28-base pair deletion was observed in all C2Q0 alleles associated with the common type I deficient complotype/haplotype; this deletion was not present in normal C2 nor in type II C2-deficient genes.

type II C2-deficient


Input: These data demonstrate that 1) type I human complement C2 deficiency is caused by a 28-base pair genomic deletion that causes skipping of exon 6 during RNA splicing, resulting in generation of a premature termination codon, 2) the 28-base pair deletion in the type I C2Q0 gene is strongly associated with the HLA haplotype/complotype A25, B18, C2Q0, BfS, C4A4, C4B2, Drw2, suggesting that all C2-deficient individuals with this haplotype/complotype will harbor the 28-base pair C2 gene deletion, and 3) type II C2 deficiency is caused by a different, as yet uncharacterized, molecular genetic defect..

type I human complement C2 deficiency

type II C2 deficiency

genetic defect


Input: Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase.

galactosemia


Input: We report here the molecular characterization of two galactosemia mutations, L74P and F171S, and one polymorphism, S135L, in human galactose-1-phosphate uridyltransferase (GALT).

galactosemia


Input: Both galactosemia mutations result in reduced enzymatic activity when reconstructed in the cDNA and overexpressed.

galactosemia


Input: The polymorphism, in contrast, has near normal activity.


Input: Both mutations affect evolutionarily conserved residues, suggesting that they are functionally important, while the polymorphism occurs in a nonconserved domain which is presumably not critical for enzymatic function.


Input: The F171S mutation is close to the putative active-site nucleophile.


Input: Our data further support the notion of molecular heterogeneity of galactosemia and suggest that galactosemia mutations and GALT polymorphisms may be useful tools in highlighting different functional domains in human GALT..

galactosemia

galactosemia


Input: Linkage relationship of C2 deficiency, HLA and glyoxalase I loci.

C2 deficiency


Input: Immunogenetic analysis of a homozygous C2-deficient individual and family members demonstrated linkage of HLA-A25, B18 and C2o.


Input: HLA-D typing showed that 5 members typed with homozygous Dw2 typing cells from an individual with C2 deficiency but not with Dw2 typing cells from 2 individuals with normal C2.

C2 deficiency


Input: The homozygous C2-deficient propositus and brother were HLA-A and B homozygous but heterozygous at the HLA-D and glyoxalase I loci.


Input: Therefore, in this family, the C2o gene is linked with two distinct haplotypes HLA-A25, B18, Dw2, GLO1 and HLA-A25, B18, D unknown, GL02.


Input: These results could be explained by an ancestral recombinant event, which occurred between the C2o locus and HLA-D locus in which C2o segregated with HLA-B.


Input: This would suggest that the locus for the C2o gene maps between HLA-B and HLA-D on the sixth chromosome..


Input: Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.

Wilms' tumor

Denys-Drash syndrome


Input: Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms tumor (nephroblastoma).

Denys-Drash syndrome

urogenital aberrations

renal failure

pseudohermaphroditism

Wilms tumor

nephroblastoma


Input: To investigate its possible role, we have analyzed the coding exons of the Wilms tumor suppressor gene (WT1) for germline mutations.

Wilms tumor


Input: In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found.

Denys-Drash syndrome


Input: Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II).


Input: These mutations directly affect DNA sequence recognition.


Input: In two families analyzed, the mutations were shown to arise de novo.


Input: Wilms tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele.

Wilms tumors

tumor


Input: Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development..

Denys-Drash syndrome


Input: Linkage analysis in X-linked adrenoleukodystrophy and application in post-and prenatal diagnosis.

X-linked adrenoleukodystrophy


Input: We have performed linkage analysis with the DNA markers DXS52 and the clotting factor VIII gene (F8C), in several large families with X-linked adrenoleukodystrophy (ALD).

X-linked adrenoleukodystrophy

ALD


Input: The tight linkage to DXS52 could be extended giving a maximal LOD score of 22.


Input: 5 at 1 cM.


Input: F8C was also tightly linked to ALD with a maximal LOD score of 7.

ALD


Input: 8 without recombination.


Input: Multipoint linkage analysis with the markers DXS304, DXS52, and F8C indicated that both the gene for ALD and for F8C are distal to DXS52.

ALD


Input: In four patients with ALD, no major structural rearrangement in the Xqter region was observed; in particular, there were no abnormalities in the vision blindness genes.

ALD

abnormalities in the vision blindness genes


Input: DNA analysis appeared to be of use in determination of the carrier status of females at risk, for the determination of the origin of the mutation in a particular family, and for prenatal diagnosis.


Input: Two distinct mutations at a single BamHI site in phenylketonuria.

phenylketonuria


Input: Classical phenylketonuria is an autosomal recessive disease caused by a deficiency of hepatic phenylalanine hydroxylase (PAH).

Classical phenylketonuria

autosomal recessive disease

deficiency of hepatic phenylalanine hydroxylase


Input: The abolition of an invariant BamHI site located in the coding sequence of the PAH gene (exon 7) led to the recognition of two new point mutations at codon 272 and 273 (272gly----stop and 273ser----phe, respectively).


Input: Both mutations were detected in north eastern France or Belgium and occurred on the background of RFLP haplotype 7 alleles.


Input: The present study supports the view that the clinical heterogeneity in PKU is accounted for by the large variety of mutant genotypes associated with PAH deficiencies..

PKU

PAH deficiencies


Input: A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates.


Input: Utilizing the CEPH reference panel and genotypic data for 53 markers, we have constructed a 20-locus multipoint genetic map of human chromosome 4.


Input: New RFLPs are reported for four loci.


Input: The map integrates a high-resolution genetic map of 4p16 into a continuous map extending to 4q31 and an unlinked cluster of three loci at 4q35.


Input: The 20 linked markers form a continuous linkage group of 152 cM in males and 202 cM in females.


Input: Likely genetic locations are provided for 25 polymorphic anonymous sequences and 28 gene-specific RFLPs.


Input: The map was constructed employing the LINKAGE and CRIMAP computational methodologies to build the multipoint map via a stepwise algorithm.


Input: A detailed 10-point map of the 4p16 region constructed from the CEPH panel provides evidence for heterogeneity in the linkage maps constructed from families segregating for Huntington disease (HD).

Huntington disease

HD


Input: It additionally provides evidence for position-specific recombination frequencies in the telomeric region of 4p..


Input: Carrier detection and prenatal diagnosis of Pelizaeus-Merzbacher disease using a combination of anonymous DNA polymorphisms and the proteolipid protein (PLP) gene cDNA.

Pelizaeus-Merzbacher disease


Input: We report carrier identification and a prenatal diagnosis using DNA polymorphisms in 2 families with X-linked Pelizaeus-Merzbacher disease (PMD).

X-linked Pelizaeus-Merzbacher disease

PMD


Input: In both families, the proteolipid protein (PLP) gene in the single affected male could be traced back to his unaffected maternal grandfather.


Input: Therefore, each family contains a new mutation.


Input: In the case of the prenatal diagnosis, the fetus was shown by cytogenetic analysis to be a female, who we predict will be a noncarrier of PMD based on her genotype with the PLP intragenic polymorphism..

PMD


Input: Identification of deletion mutations and three new genes at the familial polyposis locus.

familial polyposis


Input: Small (100-260 kb), nested deletions were characterized in DNA from two unrelated patients with familial adenomatous polyposis coli (APC).

familial adenomatous polyposis coli

APC


Input: Three candidate genes located within the deleted region were ascertained and a previous candidate gene, MCC, was shown to be located outside the deleted region.


Input: One of the new genes contained sequence identical to SRP19, the gene coding for the 19 kd component of the ribosomal signal recognition particle.


Input: The second, provisionally designated DP1 (deleted in polyposis 1), was found to be transcribed in the same orientation as MCC.


Input: Two other cDNAs, DP2 and DP3, were found to overlap, forming a single gene, DP2.


Input: 5, that is transcribed in the same orientation as SRP19.


Input: Exclusion of linkage between familial Mediterranean fever and the human serum amyloid A (SAA) gene cluster.

familial Mediterranean fever


Input: We studied the relationship between the autosomal recessive trait familial Mediterranean fever (FMF) and the serum amyloid A (SAA) genes by comparing alleles of a highly polymorphic dinucleotide repeat and a conventional restriction fragment length polymorphism (RFLP) in the SAA gene cluster in Israeli FMF kindreds.

familial Mediterranean fever

FMF

FMF


Input: By haplotype analysis, our data indicate a minimum crossover frequency of 22% between the SAA gene marker and FMF.

FMF


Input: By conventional linkage analysis this eliminates a minimum of 10.


Input: 4 cM including and surrounding the SAA gene cluster as the site of the FMF mutation although SAA proteins are prominent physiologic markers of the acute attacks.

FMF


Input: PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma.

centrocytic lymphoma


Input: Rearrangement of the BCL1 (B-cell lymphoma 1) region on chromosome 11q13 appears to be highly characteristic of centrocytic lymphoma and also is found infrequently in other B-cell neoplasms.

centrocytic lymphoma

B-cell neoplasms


Input: Rearrangement is thought to deregulate a nearby protooncogene, but transcribed sequences in the immediate vicinity of BCL1 breakpoints had not been identified.


Input: PRAD1, previously designated D11S287E, was identified on 11q13 as a chromosomal breakpoint region rearranged with the parathyroid hormone gene in a subset of parathyroid adenomas; this highly conserved putative oncogene, which encodes a novel cyclin, has been linked to BCL1 and implicated also in subsets of breast and squamous cell neoplasms with 11q13 amplification.

parathyroid adenomas

breast and squamous cell neoplasms


Input: We report pulsed-field gel electrophoresis data showing BCL1 and PRAD1 to be no more than 130 kilobases apart.


Input: PRAD1 mRNA is abundantly expressed in seven of seven centrocytic lymphomas (Kiel classification), in contrast to 13 closely related but noncentrocytic lymphomas.

centrocytic lymphomas

noncentrocytic lymphomas


Input: Three of the seven centrocytic lymphomas had detectable BCL1 DNA rearrangement.

centrocytic lymphomas


Input: Also, two unusual cases of CLL with BCL1 rearrangement overexpressed PRAD1, in contrast to five CLL controls.


Input: Thus, PRAD1 is an excellent candidate " BCL1 oncogene.


Input: " Its overexpression may be a key consequence of rearrangement of the BCL1 vicinity in B-cell neoplasms and a unifying pathogenetic feature in centrocytic lymphoma.

B-cell neoplasms

centrocytic lymphoma


Input: Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient.

metachromatic leukodystrophy

MLD


Input: Fragments of the arylsulfatase A (ARSA) gene from a patient with juvenile-onset metachromatic leukodystrophy (MLD) were amplified by PCR and ligated into MP13 cloning vectors.

metachromatic leukodystrophy

MLD


Input: Clones hybridizing with cDNA for human ARSA were selected, examined for appropriate size inserts, and used to prepare single-stranded phage DNA.


Input: Examination of the entire coding and most of the intronic sequence revealed two putative disease-related mutations.


Input: One, a point mutation in exon 3, resulted in the substitution of isoleucine by serine.


Input: Introduction of this alteration into the normal ARSA cDNA sequence resulted in a substantial decrease in ARSA activity on transient expression in cultured baby hamster kidney cells.


Input: About 5% of the control expression was observed, suggesting a small residual activity in the mutated ARSA.


Input: The second mutation, a G-to-A transition, occurred in the other allele and resulted in an altered splice-recognition sequence between exon 7 and the following intron.


Input: The mutation also resulted in the loss of a restriction site.


Input: Apparently normal levels of mRNA were generated from this allele, but no ARSA activity or immuno-cross-reactive material could be detected.


Input: A collection of DNA samples from known or suspected MLD patients, members of their families, and normal controls was screened for these mutations.

MLD


Input: Four additional individuals carrying each of the mutations were found among the nearly 100 MLD patients in the sample.

MLD


Input: Gene segregation in the original patients family was consistent with available clinical and biochemical data.


Input: No individuals homozygous for either of these two mutations were identified.


Input: However, combinations with other MLD mutations suggest that the point mutation in exon 3 does result in some residual enzyme activity and is associated with late-onset forms of the disease.

MLD


Input: The splice-site mutation following exon 7 produces late-infantile MLD when combined with other enzyme-null mutations, implying that it is completely silent enzymatically..

MLD


Input: Analysis of X-chromosome inactivation and presumptive expression of the Wiskott-Aldrich syndrome (WAS) gene in hematopoietic cell lineages of a thrombocytopenic carrier female of WAS.

Wiskott-Aldrich syndrome

WAS

WAS


Input: We report on a thrombocytopenic female belonging to a pedigree with the Wiskott-Aldrich syndrome (WAS).

thrombocytopenic

Wiskott-Aldrich syndrome

WAS


Input: Restriction fragment length polymorphism (RFLP) analysis with probe M27 beta, closely linked to the WAS gene, demonstrated that she is a carrier of WAS.

WAS

WAS


Input: Both small-sized and normal-sized platelets were present, suggesting that, unlike the vast majority of WAS carriers, she does not manifest nonrandom X-chromosome inactivation in the thrombopoietic cell lineage.

WAS


Input: Study of X-chromosome inactivation by means of RFLP and methylation analysis demonstrated that the pattern of X-chromosome inactivation was nonrandom in T lymphocytes, but random in granulocytes.


Input: While this is the first complete report on the occurrence of thrombocytopenia in a carrier female of WAS as the result of atypical lyonization, it also suggests that expression of the WAS gene occurs at (or extends up to) a later stage than the multipotent stem cell along the hematopoietic differentiation pathway..

thrombocytopenia

WAS

WAS


Input: A new mutation in the proteolipid protein (PLP) gene in a German family with Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease


Input: A C-to-T transition in exon 4 of the PLP gene was found in 2 affected males and two obligate carriers in a German family with Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease


Input: The mutation, which causes loss of an HphI site and changes amino acid 155 from threonine to isoleucine, was absent from 108 normal chromosomes.


Input: There are 5 concordances and 1 discrepancy between these results and those obtained by magnetic resonance imaging in this family..


Input: A 3-base pair in-frame deletion of the phenylalanine hydroxylase gene results in a kinetic variant of phenylketonuria.

phenylketonuria


Input: Phenylketonuria (PKU) is an autosomal recessive disease due to deficiency of a hepatic enzyme, phenylalanine hydroxylase (PAH).

Phenylketonuria

PKU

autosomal recessive disease

deficiency of a hepatic enzyme, phenylalanine hydroxylase


Input: The absence of PAH activity results in typical PKU while persistence of a residual enzyme activity gives rise to variant forms of the disease.

PKU


Input: We report here a 3-base pair in-frame deletion of the PAH gene (delta 194) in a mild variant, with markedly reduced affinity of the enzyme for phenylalanine (Km = 160 nM), and we provide functional evidence for responsibility of the deletion in the mutant phenotype.


Input: Since the deletion was located in the third exon of the gene, which presents no homology with other hydroxylases, we suggest that exon 3 is involved in the specificity of the enzyme for phenylalanine.


Input: Finally, since none of the 98 PKU patients tested were found to carry this particular deletion, our study suggests that this molecular event probably occurred recently on the background of a haplotype 2 gene in Portugal..

PKU


Input: Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism.

piebaldism


Input: Piebaldism is an autosomal dominant genetic disorder characterized by cogenital patches of skin and hair from which melanocytes are completely absent.

Piebaldism

autosomal dominant genetic disorder


Input: A similar disorder of mouse, dominant white spotting (W), results from mutations of the c-Kit protooncogene, which encodes and receptor for mast/stem cell growth factor.


Input: We identified a KIT gene mutation in a proband with classic autosomal dominant piebaldism.

piebaldism


Input: This mutation results in a Gly----Arg substitution at codon 664, within the tyrosine kinase domain.


Input: This substitution was not seen in any normal individuals and was completely linked to the piebald phenotype in the probands family.

piebald


Input: Piebaldism in this family thus appears to be the human homologue to dominant white spotting (W) of the mouse..

Piebaldism


Input: Genetic analysis of a Japanese family with normotriglyceridemic abetalipoproteinemia indicates a lack of linkage to the apolipoprotein B gene.

normotriglyceridemic abetalipoproteinemia


Input: Normotriglyceridemic abetalipoproteinemia is a rare familial disorder characterized by an isolated deficiency of apoB-100.

Normotriglyceridemic abetalipoproteinemia

familial disorder

deficiency of apoB-100


Input: We have previously reported a patient with this disease, who had normal apoB-48 but no apoB-100.


Input: To elucidate the genetic abnormalities in this family, we studied the linkage of apoB gene using three genetic markers.

genetic abnormalities


Input: The proband and her affected brother showed completely different apoB gene alleles, suggesting that the apoB gene itself is not related to this disorder in this family.


Input: By contrast, an American case had a point substitution in the apoB gene generating an in-frame stop codon.


Input: These results indicate that this disorder can be caused by defect (s) of either an apoB gene or other genes..


Input: Localisation of the gene for Norrie disease to between DXS7 and DXS426 on Xp.

Norrie disease


Input: A highly informative microsatellite marker, DXS426, which maps proximal to DXS7 in the interval Xp11.


Input: 4-Xp11 4-Xp11.


Input: 23, has been used to refine further the localisation of the gene for Norrie disease (NDP).

Norrie disease

NDP


Input: The results from a multiply informative crossover localize the NDP gene proximal to DXS7.

NDP


Input: In conjunction with information from 2 NDP patients who have a deletion for DXS7 but not for DSX426, our data indicate that the NDP gene lies between DXS7 and DXS426 on proximal Xp.

NDP

NDP


Input: Aberrant splicing of phenylalanine hydroxylase mRNA: the major cause for phenylketonuria in parts of southern Europe.

phenylketonuria


Input: We report a mutation within the phenylalanine hydroxylase (PAH) gene that causes aberrant splicing of the mRNA and that is in tight association with chromosomal haplotypes 6, 10, and 36.


Input: Because of the high frequency of these particular haplotypes in Bulgaria, Italy, and Turkey, it appears to be one of the more frequent defects in the PAH gene causing classical phenylketonuria in this part of Europe.

phenylketonuria


Input: The mutation is a G to A transition at position 546 in intron 10 of the PAH gene, 11 bp upstream from the intron 10/exon 11 boundary.


Input: It activates a cryptic splice site and results in an in-frame insertion of 9 nucleotides between exon 10 and exon 11 of the processed mRNA.


Input: Normal amounts of liver PAH protein are present in homozygous patients, but no catalytic activity can be detected.


Input: This loss of enzyme activity is probably caused by conformational changes resulting from the insertion of three additional amino acids (Gly-Leu-Gln) between the normal sequences encoded by exon 10 and exon 11..


Input: Gardner syndrome in a boy with interstitial deletion of the long arm of chromosome 5.

Gardner syndrome


Input: We described a 15-year-old boy with Gardner syndrome (GS), mental retardation, and craniofacial abnormalities.

Gardner syndrome

GS

mental retardation

craniofacial abnormalities


Input: High-resolution banding analysis showed an interstitial deletion of the long arm of chromosome 5 (q22. 1----q31 1----q31. 1).


Input: The breakpoints in the present case and in 3 previously reported 5q-patients with adenomatous polyposis coli suggest that the gene responsible for GS/or familial polyposis coli (FPC) is in the 5q22 region, a result consistent with the findings of linkage studies

adenomatous polyposis coli

GS

familial polyposis coli

FPC


Input: Huntington disease and childhood-onset Tourette syndrome.

Huntington disease

Tourette syndrome


Input: A 40-year-old man with childhood-onset Tourette syndrome (TS) developed Huntington disease (HD).

Tourette syndrome

TS

Huntington disease

HD


Input: We believe this to be the first reported case of childhood-onset TS with adult onset HD.

TS

HD


Input: Discovery of other cases with both disorders may provide clues to the pathophysiology of both conditions..


Input: Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.

Tay-Sachs disease


Input: The rapid identification of mutations causing Tay-Sachs disease requires the capacity to readily screen the regions of the HEXA gene most likely to be affected by mutation.

Tay-Sachs disease


Input: We have sequenced the portions of the introns flanking each of the 14 HEXA exons in order to specify oligonucleotide primers for the PCR-dependent amplification of each exon and splice-junction sequence.


Input: The amplified products were analyzed, by electrophoresis in nondenaturing polyacrylamide gels, for the presence of either heteroduplexes, derived from the annealing of normal and mutant DNA strands, or single-strand conformational polymorphisms (SSCP), derived from the renaturation of single-stranded DNA.


Input: Five novel mutations from Tay-Sachs disease patients were detected a 5-bp deletion of TCTCC in IVS-9; a 2-bp deletion of TG in exon 5; G78 to A, giving a stop codon in exon 1; G533 to T in exon 5, producing the third amino acid substitution detected at this site; and G to C at position 1 of IVS-2, expected to produce abnormal splicing.

Tay-Sachs disease


Input: In addition, two mutations, (G1496 to A in exon 13 and a 4-bp insertion in exon 11) that have previously been reported were identified..


Input: Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase.

galactosemia


Input: Galactosemia is an autosomal recessive disorder of human galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT).

Galactosemia

autosomal recessive disorder of human galactose metabolism

deficiency of the enzyme galactose-1-phosphate uridyl transferase


Input: The molecular basis of this disorder is at present not well understood.


Input: We report here two missense mutations which result in low or undetectable enzymatic activity.


Input: First, we identified at nucleotide 591 a transition which substitutes glutamine 188 by arginine.


Input: The mutated glutamine is not only highly conserved in evolution (conserved also in Escherichia coli and Saccharomyces cerevisiae), but is also two amino acid residues downstream from the active site histidine-proline-histidine triad and results in about 10% of normal enzymatic activity.


Input: The arginine 188 mutation is the most common galactosemia mutation characterized to date.

galactosemia


Input: It accounts for one-fourth of the galactosemia alleles studied.

galactosemia


Input: Second, we report the substitution of arginine 333 by tryptophan, caused by a transition at nucleotide 1025.


Input: The area surrounding this missense mutation is the most highly conserved domain in the homologous enzymes from E. coli, yeast, and humans, and this mutation results in undetectable enzymatic activity, suggesting that this is a severe mutation.


Input: This second mutation appears to be rare, since it was found only in the patient we sequenced.


Input: Our data provide further evidence for the heterogeneity of galactosemia at the molecular level, heterogeneity which might be related to the variable clinical outcome observed in this disorder..

galactosemia


Input: Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification.

Hypoxanthine-guanine phosphoribosyltransferase deficiency


Input: The Lesch-Nyhan syndrome is a severe X chromosome-linked human disease caused by a virtual absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity.

Lesch-Nyhan syndrome

X chromosome-linked human disease

absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity


Input: A partial deficiency in the activity of this enzyme can result in gouty arthritis.

gouty arthritis


Input: To determine the genetic basis for reduction or loss of enzyme activity, we have amplified and sequenced the coding region of HPRT cDNA from four patients one with Lesch-Nyhan syndrome (HPRTPerth) and three with partial deficiencies of HPRT activity, which have been designated HPRTUrangan, HPRTSwan and HPRTToowong.

Lesch-Nyhan syndrome

partial deficiencies of HPRT activity


Input: In all four patients, the only mutation identified was a single base substitution in exons 2 or 3 of the coding region, which in each case predicts a single amino acid substitution in the translated protein.


Input: Each base change was confirmed by allele-specific amplification of the patients genomic DNA.


Input: It is interesting to note that the mutation found for HPRTPerth is identical to that reported for HPRTFlint.


Input: It appears that the two mutations are de novo events..


Input: Molecular and metabolic basis for the metabolic disorder normotriglyceridemic abetalipoproteinemia.

metabolic disorder normotriglyceridemic abetalipoproteinemia


Input: We have previously described a disorder, normotriglyceridemic abetalipoproteinemia, that is characterized by the virtual absence of plasma low density lipoproteins and complete absence of apoB-100, but with apparently normal secretion of triglyceride-rich lipoproteins containing apoB-48.

normotriglyceridemic abetalipoproteinemia


Input: The patients plasma lipoproteins were shown on polyacrylamide gels and by antibody mapping to have a new truncated apoB variant, apoB-50, circulating along with her apoB-48.


Input: We have found this individual to be homozygous for a single C-to-T nucleotide substitution at apoB codon 2252, which produces a premature in-frame stop codon.


Input: Thus, this is a rare example of homozygous hypobetalipoproteinemia.

homozygous hypobetalipoproteinemia


Input: Electron photomicrographs revealed that the diameters of particles in the d less than 1.


Input: 006 g/ml lipoprotein fraction, in both the postprandial and postabsorptive state, are bimodally distributed.


Input: The molar ratio of apoE to apoB in these particles is 3.


Input: 5 1, similar to normal VLDL.


Input: The plasma LDL interval contains both spherical and cuboidal particles.


Input: Autologous reinfusion of labeled d less than 1.


Input: 006 g/ml lipoproteins showed exponential disappearance from plasma, with an apparent half-removal time of 50 min, somewhat slower than for normal chylomicrons but within the normal range for VLDL.


Input: The calculated production rate for apoB was within the normal range in this subject.


Input: A single origin of phenylketonuria in Yemenite Jews.

phenylketonuria


Input: Phenylketonuria (PKU) is a metabolic disease caused by recessive mutations of the gene encoding the hepatic enzyme phenylalanine hydroxylase (PAH).

Phenylketonuria

PKU

metabolic disease


Input: The incidence of PKU varies widely across different geographic areas, and is highest (about 1 in 5, 000 live births) in Ireland and western Scotland, and among Yemenite Jews.

PKU


Input: A limited number of point mutations account for most of the PKU cases in the European population.

PKU


Input: Here we report that a single molecular defect--a deletion spanning the third exon of the PAH gene--is responsible for all the PKU cases among the Yemenite Jews.

PKU


Input: Examination of a random sample of Yemenite Jews using a molecular probe that detects the carriers of this deletion indicated a high frequency of the defective gene in this community.


Input: Although the deleted PAH gene was traced to 25 different locations throughout Yemen, family histories and official documents of the Yemenite Jewish community showed that the common ancestor of all the carriers of this genetic defect lived in Sana, the capital of Yemen, before the eighteenth century..

genetic defect


Input: Linkage of aspartylglucosaminuria (AGU) to marker loci on the long arm of chromosome 4.

aspartylglucosaminuria

AGU


Input: Aspartylglucosaminuria (AGU) is caused by deficient activity of the enzyme aspartylglucosaminidase (AGA).

Aspartylglucosaminuria

AGU


Input: The structural gene for AGA has been assigned to the region 4q21-qter of chromosome 4.


Input: We have studied the map position of the AGU locus in relation to other marker loci on the long arm of chromosome 4 using linkage analyses.


Input: Restriction fragment length polymorphism alleles for the ADH2, ADH3, EGF, FG alpha and FG beta loci and blood group antigens for the MNS locus were determined in a panel of 12 Finnish AGU families.

AGU


Input: The heterozygous family members were identified by reduced activity of AGA in lymphocytes.


Input: Linkage studies were performed using both pairwise and multipoint analyses.


Input: Loose linkage of the AGU locus to the FG and MNS loci was observed (z = 1. 16, z = 1. 39, respectively).

AGU


Input: Multipoint analysis to the fixed map [ADH-(0. 03)-EGF-(0. 35)-FG-(0. 11)-MNS] suggests that the location of the AGU locus is 0.


Input: 30 recombination units distal to MNS (z = 3. 03).


Input: The order cen-ADH-EGF-FG-MNS-AGU is 35 times more likely than the next best order cen-ADH-EGF-AGU-FG-MNS.


Input: Linkage relationships of the apolipoprotein C1 gene and a cytochrome P450 gene (CYP2A) to myotonic dystrophy.

myotonic dystrophy


Input: We have studied the genetic linkage of two markers, the apolipoprotein C1 (APOC1) gene and a cytochrome P450 (CYP2A) gene, in relation to the gene for myotonic dystrophy (DM).

myotonic dystrophy

DM


Input: A peak lod score of 9.


Input: 29 at 2 cM was observed for APOC1-DM, with a lod score of 8.


Input: 55 at 4 cM for CYP2A-DM.


Input: These two markers also show close linkage to each other (theta max = 0. 05, Zmax = 9. 09).


Input: From examination of the genotypes of the recombinant individuals, CYP2A appears to map proximal to DM because in one recombinant individual CYP2A, APOC2 and CKMM had all recombined with DM.


Input: Evidence from another CYP2A-DM recombinant individual places CYP2A proximal to APOC2 and CKMM.


Input: Localisation of CYP2A on a panel of somatic cell hybrids also suggests that it is proximal to DM and APOC2/C1/E gene cluster.


Input: Genetic linkage map of six polymorphic DNA markers around the gene for familial adenomatous polyposis on chromosome 5.

familial adenomatous polyposis


Input: A genetic linkage map of six polymorphic DNA markers close to the gene (APC) for familial adenomatous polyposis (FAP) on chromosome 5q is reported.

familial adenomatous polyposis

FAP


Input: One hundred fifty-five typed members of nine FAP kindred provided more than 90 meioses for linkage analysis.

FAP


Input: A number of crucial recombination events have been identified which are informative at three or more loci, allowing confident ordering of parts of the map.


Input: There was no evidence of genetic heterogeneity, with all families showing linkage of at least one chromosome 5 marker to the gene.


Input: Recombination data and two-point linkage analysis support a locus order of centromere-pi 227-C11P11-ECB27-L5.


Input: 62-APC-EF5 62-APC-EF5.


Input: 44-YN5 44-YN5.


Input: 48-telomer e, although EF5.


Input: 44 could lie in the interval L5.


Input: 62-APC or ECB27-L5.


Input: No recombinants were identified between APC and either EF5.


Input: 44 or YN5.


Input: 48, but published deletion mapping in colorectal carcinomas and linkage analysis in FAP suggest that YN5.

colorectal carcinomas

FAP


Input: 48 is 1-3 cM from APC.


Input: The present study suggests that YN5.


Input: 48 and L5.


Input: 62 delineate a small region of chromosome 5 within which the EF5.


Input: 44 locus lies very close to the APC gene.

APC


Input: These data not only allow use of flanking markers for presymptomatic diagnosis of FAP but also provide a high-density map of the region for isolation of the APC gene itself and for further assessment of the role of chromosome 5 deletions in the biology of sporadic colorectal cancer.

FAP

APC

colorectal cancer


Input: Serum amyloid A and P protein genes in familial Mediterranean fever.

familial Mediterranean fever


Input: Two recent studies have suggested the involvement of serum amyloid A (SAA) and P (APCS) genes in familial Mediterranean fever (MEF).

familial Mediterranean fever

MEF


Input: To test the role of SAA and APCS in MEF and MEF-amyloidosis, we studied 17 informative families (15 Armenians, 2 non-Ashkenazi Jews) and 8 MEF patients with amyloidosis using a candidate gene approach.

MEF

MEF-amyloidosis

MEF

amyloidosis


Input: No evidence for any MEF-associated polymorphism was found in any of the 41 Armenian and Jewish MEF patients tested.

MEF

MEF


Input: Our family studies allowed us to rule out tight linkage between SAA and MEF (lod score =-2. 16, theta less than or equal to 0. 06).

MEF


Input: For APCS we found that the allele frequency in the MEF-amyloidosis patients was similar to that in 18 unrelated MEF patients without amyloidosis and their 33 healthy parents.

MEF-amyloidosis

MEF

amyloidosis


Input: Some Mexican glucose-6-phosphate dehydrogenase variants revisited.


Input: Glucose-6-phosphate dehydrogenase (G6PD) deficiency appears to be fairly common in Mexico.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency


Input: We have now examined the DNA of three previously reported electrophoretically fast Mexican G6PD variants,-G6PD Distrito Federal, G6PD Tepic, and G6PD Castilla.


Input: All three of these variants, believed on the basis of biochemical characterization and population origin to be unique, have the G----A transition at nucleotide 202 and the A----G transition at nucleotide 376, mutations that we now recognize to be characteristic of G6PD A-.


Input: Two other Mexican males with G6PD deficiency were found to have the same mutation.

G6PD deficiency


Input: All five have the (NlaIII/FokI/PvuII/PstI) haplotype characteristic of G6PD A-in Africa.


Input: Since the PvuII + genotype seems to be rare in Europe, we conclude that all of these G6PD A-genes had their ancient origin in Africa, although in many of the Mexican patients with G6PD A-202A/376G the gene may have been imported more recently from Spain, where this variant, formerly known as G6PD Betica, is also prevalent..


Input: Hereditary deficiency of C5 in association with discoid lupus erythematosus.

deficiency of C5

discoid lupus erythematosus


Input: A 29-year-old woman with discoid lupus erythematosus had undetectable classic pathway complement activity.

discoid lupus erythematosus


Input: Hypocomplementemia was due to selective deficiency of C5.

Hypocomplementemia

deficiency of C5


Input: One of her children was also deficient.


Input: To our knowledge this is the first documented case of an association between discoid lupus erythematosus and C5 deficiency..

discoid lupus erythematosus

C5 deficiency


Input: Founder effect of a prevalent phenylketonuria mutation in the Oriental population.

phenylketonuria


Input: A missense mutation has been identified in the human phenylalanine hydroxylase [PAH; phenylalanine 4-monooxygenase; L-phenylalanine, tetrahydrobiopterin oxygen oxidoreductase (4-hydroxylating), EC 1. 14. 16. 1] gene in a Chinese patient with classic phenylketonuria (PKU).

phenylketonuria

PKU


Input: A G-to-C transition at the second base of codon 413 in exon 12 of the gene results in the substitution of Pro413 for Arg413 in the mutant protein.


Input: This mutation (R413P) results in negligible enzymatic activity when expressed in heterologous mammalian cells and is compatible with a classic PKU phenotype in the patient.

PKU


Input: Population genetic studies reveal that this mutation is tightly linked to restriction fragment length polymorphism haplotype 4, which is the predominant haplotype of the PAH locus in the Oriental population.


Input: It accounts for 13.


Input: 8% of northern Chinese and 27% of Japanese PKU alleles, but it is rare in southern Chinese (2. 2%) and is absent in the Caucasian population.

PKU


Input: The data demonstrate unambiguously that the mutation occurred after racial divergence of Orientals and Caucasians and suggest that the allele has spread throughout the Orient by a founder effect.


Input: Previous protein polymorphism studies in eastern Asia have led to the hypothesis that " northern Mongoloids " represented a founding population in Asia.


Input: Our results are compatible with this hypothesis in that the PKU mutation might have occurred in northern Mongoloids and subsequently spread to the Chinese and Japanese populations.

PKU


Input: Glucose/galactose malabsorption caused by a defect in the Na +/glucose cotransporter.

Glucose/galactose malabsorption


Input: Glucose/galactose malabsorption (GGM) is an autosomal recessive disease manifesting within the first weeks of life and characterized by a selective failure to absorb dietary glucose and galactose from the intestine.

Glucose/galactose malabsorption

GGM

autosomal recessive disease


Input: The consequent severe diarrhoea and dehydration are usually fatal unless these sugars are eliminated from the diet.

diarrhoea

dehydration


Input: Intestinal biopsies of GGM patients have revealed a specific defect in Na (+)-dependent absorption of glucose in the brush border.

GGM


Input: Normal glucose absorption is mediated by the Na +/glucose cotransporter in the brush border membrane of the intestinal epithelium.


Input: Cellular influx is driven by the transmembrane Na + electrochemical potential gradient; thereafter the sugar moves to the blood across the basolateral membrane via the facilitated glucose carrier.


Input: We have previously cloned and sequenced a Na +/glucose cotransporter from normal human ileum and shown that this gene, SGLT1, resides on the distal q arm of chromosome 22.


Input: We have now amplified SGLT1 complementary DNA and genomic DNA from members of a family affected with GGM by the polymerase chain reaction.

GGM


Input: Sequence analysis of the amplified products has revealed a single missense mutation in SGLT1 which cosegregates with the GGM phenotype and results in a complete loss of Na (+)-dependent glucose transport in Xenopus oocytes injected with this complementary RNA..

GGM


Input: A de novo unbalanced reciprocal translocation identified as paternal in origin in the Prader-Willi syndrome.

Prader-Willi syndrome


Input: Interstitial cytogenetic deletions involving the paternally derived chromosome 15q11-13 have been described in patients with the Prader-Willi syndrome (PWS).

Prader-Willi syndrome

PWS


Input: We report a child with PWS and a de novo unbalanced karyotype-45, XY,-9,-15, + der (9) t (9; 15) (q34; q13).

PWS


Input: Molecular studies with the DNA probe pML34 confirmed that only a single Prader Willi critical region (PWCR 15q11. 2-q12) copy was present.

Prader Willi


Input: Hybridisation of patient and parental DNA with the multi-allelic probe CMW1, which maps to pter-15q13, showed that the chromosome involved in the translocation was paternal in origin.


Input: This is the first example of a paternally-derived PWCR allele loss caused by an unbalanced translocation that has arisen de novo.


Input: Localisation of the myotonic dystrophy locus to 19q13. 2-19q13. 3 and its relationship to twelve polymorphic loci on 19q.

myotonic dystrophy


Input: The order of fourteen polymorphic markers localised to the long arm of human chromosome 19 has been established by multipoint mapping in a set of 40 CEPH (Centre dEtude de Polymorphisme Humain, Paris) reference families.


Input: We report here the linkage relationship of the myotonic dystrophy (DM) locus to twelve of these markers as studied in 45 families with DM.

myotonic dystrophy

DM

DM


Input: The resulting genetic map is supported by the localisation of the DNA markers in a panel of somatic cell hybrids.


Input: Ten of the twelve markers have been shown to be proximal to the DM gene and two, PRKCG and D19S22, distal but at distances of approximately 25 cM and 15 cM, respectively.

DM


Input: The closest proximal markers are APOC2 (apolipoprotein C-II) and CKM (creatine kinase, muscle) approximately 3 cM and 2 cM from the DM gene respectively, in the order APOC2-CKM-DM.

DM


Input: The distance between APOC2, CKM and DM (of the order of 2 million base pairs) and their known orientation should permit directional chromosome walking and jumping.

DM


Input: The data presented here should enable us to determine whether or not new markers are distal to APOC2/CKM and thus potentially flank the DM gene..

DM


Input: Localization of histidase to human chromosome region 12q22----q24. 1 and mouse chromosome region 10C2----D1.


Input: The human gene for histidase (histidine ammonia-lyase; HAL), the enzyme deficient in histidinemia, was assigned to human chromosome 12 by Southern blot analysis of human X mouse somatic cell hybrid DNA.

histidinemia


Input: The gene was sublocalized to region 12q22----q24.


Input: 1 by in situ hybridization, using a human histidase cDNA.


Input: The homologous locus in the mouse (Hal) was mapped to region 10C2----D1 by in situ hybridization, using a cell line from a mouse homozygous for a 1.


Input: 10 Robertsonian translocation.


Input: These assignments extend the conserved syntenic region between human chromosome 12 and mouse chromosome 10 that includes the genes for phenylalanine hydroxylase, gamma interferon, peptidase, and citrate synthase.


Input: The localization of histidase to mouse chromosome 10 suggests that the histidase regulatory locus (Hsd) and the histidinemia mutation (his), which are both known to be on chromosome 10, may be alleles of the histidase structural gene locus.


Input: Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects.

Lesch-Nyhan syndrome


Input: Hypoxanthine--guanine phosphoribosyltransferase (HPRT) is a purine salvage enzyme that catalyzes the conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate.


Input: Previous studies of mutant HPRT proteins analyzed at the molecular level have shown a significant heterogeneity.


Input: This investigation further verifies this heterogeneity and identifies insertions, deletions, and point mutations.


Input: The direct sequencing of the polymerase chain reaction-amplified product of reverse-transcribed HPRT mRNA enabled the rapid identification of the mutations found in 17 previously uncharacterized cell lines derived from patients with the Lesch-Nyhan syndrome..

Lesch-Nyhan syndrome


Input: Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family.

adrenoleukodystrophy

adrenomyeloneuropathy


Input: We present a large kindred that contained patients with either adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN).

adrenoleukodystrophy

ALD

adrenomyeloneuropathy

AMN


Input: The pedigree clearly supported the X-linked mode of inheritance of the nonneonatal form of ALD/AMN.

ALD

AMN


Input: Analysis with DNA markers at Xq28 suggested segregation of both ALD and AMN with an identical haplotype.

ALD

AMN


Input: This indicated that nonneonatal ALD and AMN are caused by a mutation in the same gene at Xq28.

ALD

AMN


Input: It showed, furthermore, that phenotypic differences between ALD and AMN are not necessarily the consequence of allelic heterogeneity due to different mutations within the same gene.

ALD

AMN


Input: The maximal lod score for linkage of the ALD/AMN gene and the multiallelic anonymous DNA marker at DXS52 was 3.

ALD

AMN


Input: 0 at a recombination fraction of 0.


Input: This made a prenatal or presymptomatic diagnosis and heterozygote detection by DNA analysis with this marker reliable.


Input: Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy.

Duchenne muscular dystrophy


Input: One of female MZ twins presented with muscular dystrophy.

muscular dystrophy


Input: Physical examination, creatine phosphokinase levels, and muscle biopsy were consistent with Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy

DMD


Input: However, because of her sex she was diagnosed as having limb-girdle muscular dystrophy.

limb-girdle muscular dystrophy


Input: With cDNA probes to the DMD gene, a gene deletion was detected in the twins and their mother.

DMD


Input: The de novo mutation which arose in the mother was shown by novel junction fragments generated by HindIII, PstI, or TaqI when probed with cDNA8.


Input: Additional evidence of a large gene deletion was given by novel SfiI junction fragments detected by probes p20, J-Bir, and J-66 on pulsed-field gel electrophoresis (PFGE).


Input: Immunoblot analysis of muscle from the affected twin showed dystrophin of normal size but of reduced amount.


Input: Immunofluorescent visualization of dystrophin revealed foci of dystrophin-positive fibers adjacent to foci of dystrophin-negative fibers.


Input: These data indicate that the affected twin is a manifesting carrier of an abnormal DMD gene, her myopathy being a direct result of underexpression of dystrophin.

DMD

myopathy


Input: Cytogenetic analysis revealed normal karyotypes, eliminating the possibility of a translocation affecting DMD gene function.

DMD


Input: Both linkage analysis and DNA fingerprint analysis revealed that each twin has two different X chromosomes, eliminating the possibility of uniparental disomy as a mechanism for DMD expression.

uniparental disomy

DMD


Input: On the basis of methylation differences of the paternal and maternal X chromosomes in these MZ twins, we propose uneven lyonization (X chromosome inactivation) as the underlying mechanism for disease expression in the affected female..


Input: Adrenoleukodystrophy and adrenomyeloneuropathy associated with partial adrenal insufficiency in three generations of a kindred.

Adrenoleukodystrophy

adrenomyeloneuropathy

adrenal insufficiency


Input: Four cases of adrenoleukodystrophy (ALD) and one case of adrenomyeloneuropathy (AMN) have developed in a kindred over three generations demonstrating that AMN is a clinical variant of ALD.

adrenoleukodystrophy

ALD

adrenomyeloneuropathy

AMN

AMN

ALD


Input: Pituitary-adrenal function studies were performed in 10 family members, including two affected males and four females identified as carriers of ALD/AMN.

ALD

AMN


Input: No pituitary-adrenal abnormality was found in the carriers.

pituitary-adrenal abnormality


Input: However, basal morning plasma adrenocorticotropic hormone (ACTH) levels were markedly elevated in the two males with ALD and AMN, despite the fact that they had no clinical signs of adrenal insufficiency and that morning plasma cortisol levels and their response to maximal exogenous ACTH stimulation appeared to be normal.

ALD

AMN

adrenal insufficiency


Input: In addition, the integrated 24-hour response to the administration were also subnormal in these two cases.


Input: Thus, people with ALD and AMN may have subclinical partial adrenocrotical insufficiency.

ALD

AMN

adrenocrotical insufficiency


Input: No other endocrinologic dysfunction was identified..

endocrinologic dysfunction


Input: Regional localisation of the Friedreich ataxia locus to human chromosome 9q13----q21. 1.

Friedreich ataxia


Input: We have previously assigned the Friedreich ataxia locus (FRDA) to chromosome 9; the current maximal lod score between FRDA and MCT112 (D9S15) is greater than 50 at a recombination fraction of theta = 0.

Friedreich ataxia


Input: The physical assignment of the locus defined by MCT112, and hence FRDA, has not been determined, although linkage analysis of MCT112 with other chromosome 9 markers inferred a location close to the centromere.


Input: We have used in situ hybridisation with MCT112, a corresponding cosmid MJ1, and DR47 (D9S5), coupled with mapping studies on hybrid cell panels, to define more precisely the location of the disease locus.


Input: The in situ location of all three probes is 9q13----q21.


Input: 1, distal to the variable heterochromatin region.


Input: Physical assignment of FRDA will allow us to identify hybrid cell lines containing the mutated gene.


Input: Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.


Input: BACKGROUND AND METHODS.


Input: The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins.


Input: We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene.

CETP deficiency


Input: To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis.


Input: RESULTS.


Input: We found the same CETP gene mutation in four families from three different regions of Japan.


Input: Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype.


Input: Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [+/-SD], 7. 01 +/-0. 83 mmol per liter), markedly increased levels of HDL cholesterol (4. 24 +/-1. 01 mmol per liter) and apolipoprotein A-I, and decreased levels of low-density lipoprotein cholesterol (1. 99 +/-0. 80 mmol per liter) and apolipoprotein B.

CETP deficiency

hypercholesterolemia


Input: Members heterozygous for the deficiency (n = 20), whose CETP levels were in the lower part of the normal range, had moderately increased levels of HDL cholesterol and apolipoprotein A-I and an increased ratio of HDL subclass 2 to HDL subclass 3, as compared with unaffected family members (1. 5 +/-0. 8 vs. 0. 7 +/-0. 4).


Input: CETP deficiency was not found in six unrelated subjects with elevated HDL cholesterol levels who were from different parts of the United States.

CETP deficiency


Input: CONCLUSIONS.


Input: CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan, possibly because of a founder effect.

CETP deficiency


Input: The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2.


Input: There was no evidence of premature atherosclerosis in the families with CETP deficiency.

premature atherosclerosis

CETP deficiency


Input: In fact, the lipoprotein profile of persons with CETP deficiency is potentially antiatherogenic and may be associated with an increased life span.

CETP deficiency


Input: Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region.

ataxia-telangiectasia


Input: We recently mapped the gene for ataxia-telangiectasia group A (ATA) to chromosome 11q22-23 by linkage analysis, using the genetic markers THY1 and pYNB3.

ataxia-telangiectasia


Input: 12 (D11S144).