Input: The most likely order was cent-AT-S144-THY1.


Input: The present paper describes further mapping of the AT locus by means of a panel of 10 markers that span approximately 60 cM in the 11q22-23 region centered around S144 and THY1.

AT


Input: Location scores indicate that three contiguous subsegments within the [S144-THY1] segment, as well as three contiguous segments telomeric to THY1, are each unlikely to contain the AT locus, while the more centromeric [STMY-S144] segment is most likely to contain the AT locus.

AT

AT


Input: These data, together with recent refinements in the linkage and physical maps of 11q22-23, place the AT locus at 11q23.

AT


Input: Recurrent meningitis in a patient with congenital deficiency of the C9 component of complement.

meningitis

congenital deficiency of the C9 component of complement


Input: First case of C9 deficiency in Europe.

C9 deficiency


Input: We describe the first cases, to our knowledge, of C9 deficiency in Europe that were detected in a Swiss family, of which two members--one with a complete deficiency and the other with approximately half-normal C9 levels--experienced bacterial meningitis.

C9 deficiency

bacterial meningitis


Input: The index patient, a 56-year-old white man with a history of purulent meningitis at the age of 23 years, presented with an acute meningococcal meningitis.

purulent meningitis

acute meningococcal meningitis


Input: No impairment of cellular immunity or immunoglobulin deficiency could be found.

impairment of cellular immunity

immunoglobulin deficiency


Input: Complement assays showed a complete deficiency of the C9 component, while the other individual component levels were normal and the hemolytic activity (measured using the CH50 assay) was only slightly reduced.

complete deficiency of the C9 component


Input: A family study revealed complete C9 deficiency in the patients healthy brother and half-normal C9 concentrations in his sister, his son (who also had experienced an episode of bacterial meningitis), and his niece, consistent with an inherited C9 deficiency.

complete C9 deficiency

bacterial meningitis

C9 deficiency


Input: This first case of recurrent meningitis in a white patient with complete C9 deficiency suggests that this complement defect may also be a risk factor for bacterial, especially neisserial, infections..

recurrent meningitis

complete C9 deficiency

complement defect

bacterial, especially neisserial, infections


Input: Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction.

DMD

BMD


Input: We describe oligonucleotide primer sequences that can be used to amplify eight exons plus the muscle promoter of the dystrophin gene in a single multiplex polymerase chain reaction (PCR).


Input: When used in conjunction with an existing primer set, these two multiplex reactions detect about 98% of deletions in patients with Duchenne or Becker muscular dystrophy (DMD, BMD).

Duchenne or Becker muscular dystrophy

DMD

BMD


Input: Furthermore, these primers amplify most of the exons in the deletion prone " hot spot " region around exons 44 to 53, allowing determination of deletion endpoints and prediction of mutational effects on the translational reading frame.


Input: Thus, use of these PCR-based assays will allow deletion detection and prenatal diagnosis for most DMD/BMD patients in a fraction of the time required for Southern blot analysis..

DMD

BMD


Input: Genetic heterogeneity at the glucose-6-phosphate dehydrogenase locus in southern Italy: a study on a population from the Matera district.


Input: Glucose-6-phosphate dehydrogenase (G6PD) has been analyzed by gel electrophoresis and by quantitative assay in an unselected sample of 1524 schoolboys from the province of Matera (Lucania) in southern Italy.


Input: We have identified 43 subjects with a G6PD variant.


Input: Of these, 31 had severe G6PD deficiency, nine had mild to moderate deficiency, and three had a non-deficient electrophoretic variant.

G6PD deficiency


Input: The overall rate of G6PD deficiency was 2.

G6PD deficiency


Input: The frequency of G6PD deficiency, ranging from 7.

G6PD deficiency


Input: 2% on the Ionian Coast to zero on the eastern side of the Lucanian Apennines, appears to be inversely related to the distance of each town examined from the Ionian Coast, suggesting that this geographic distribution may reflect, at least in part, gene flow from Greek settlers.


Input: Biochemical characterization has shown that most of the G6PD deficiency in this population is accounted for by G6PD Mediterranean.

G6PD deficiency


Input: In addition, we have found several examples of two other known polymorphic variants (G6PD Cagliari and G6PD A-); three new polymorphic variants, G6PD Metaponto (class III), G6PD Montalbano (class III), and G6PD Pisticci (class IV); and two sporadic variants, G6PD Tursi (class III) and G6PD Ferrandina (class II).


Input: These data provide further evidence for the marked genetic heterogeneity of G6PD deficiency within a relatively narrow geographic area and they prove the presence in the Italian peninsula of a gene (GdA-) regarded as characteristically African.

G6PD deficiency


Input: Deficiency of the murine fifth complement component (C5).

Deficiency of the murine fifth complement component (C5)


Input: A 2-base pair gene deletion in a 5'-exon.


Input: To ascertain the molecular mechanism that causes murine C5 deficiency, genomic and cDNA libraries were constructed from mouse liver DNA and mRNA employing the congenic strains B10.

C5 deficiency


Input: D2/nSnJ and B10.


Input: D2/oSnJ that are sufficient and deficient for C5, respectively.

deficient for C5


Input: Genomic fragments were isolated which correspond to PvuII and HindIII restriction fragment length polymorphisms associated with C5 deficiency.

C5 deficiency


Input: Sequence analyses demonstrated that each of these polymorphisms resulted from single base pair substitutions and that neither substitution would probably cause or contribute to the C5 deficiency.

C5 deficiency


Input: Sequence analyses of C5 sufficient and deficient cDNAs revealed a 2 base-pair deletion in the deficient cDNAs.


Input: The " TA " deletion was located near the 5 end of the cDNA.


Input: This deletion shifts the reading frame of the C5 mRNA so that the termination codon UGA is present 4 base pairs downstream from the deletion.


Input: Genomic DNA was amplified and sequenced corresponding to the area surrounding the 2-base pair deletion.


Input: Six C5-deficient strains, A/HeJ, AKR/J, DBA/2J, NZB/B1NJ, SWR/J, and B10.


Input: D2/oSnJ, and four C5-sufficient strains, Balb/CJ, C57Bl/6J, DBA/1J, and B10.


Input: D2/nSnJ, were analyzed.


Input: The sequencing data revealed that the 2 base pairs were deleted from the C5 gene of each deficient mouse tested but not from the C5 gene of any sufficient mouse.


Input: These data demonstrate that 1) there is an identical 2-base pair deletion in an exon of the C5 gene in several different C5-deficient mouse strains; 2) the mRNA transcribed from the C5D gene retains this deletion; and 3) this mutation should result in C5 protein deficiency.

C5 protein deficiency


Input: Molecular genetics of PKU in eastern Europe: a nonsense mutation associated with haplotype 4 of the phenylalanine hydroxylase gene.

PKU


Input: Phenylketonuria (PKU) is a genetic disorder secondary to a deficiency of hepatic phenylalanine hydroxylase (PAH).

Phenylketonuria

PKU

genetic disorder

deficiency of hepatic phenylalanine hydroxylase


Input: Several mutations in the PAH gene have recently been reported, and linkage disequilibrium was observed between RFLP haplotypes and specific mutations.


Input: A new molecular lesion has been identified in exon 7 of the PAH gene in a Hungarian PKU patient by direct sequencing of PCR-amplified DNA.

molecular lesion

PKU


Input: The C-to-T transition causes the substitution of Arg243 to a termination codon, and the mutant allele is associated with haplotype 4 of the PAH gene.


Input: The mutation is present in two of nine mutant haplotype 4 alleles among Eastern Europeans and is not present among Western Europeans and Asians.


Input: The rarity of this mutant allele and its restricted geographic distribution suggest that the mutational event occurred recently on a normal haplotype 4 background in Eastern Europe..


Input: The red-green visual pigment gene region in adrenoleukodystrophy.

adrenoleukodystrophy


Input: Although recent data established that a specific very-long-chain fatty acyl-CoA synthetase is defective in X-linked adrenoleukodystrophy (ALD), the ALD gene is still unidentified.

X-linked adrenoleukodystrophy

ALD

ALD


Input: The ALD locus has been mapped to Xq28, like the red and green color pigment genes.

ALD


Input: Abnormal color vision has been observed in 12 of 27 patients with adrenomyeloneuropathy (AMN), a milder form of ALD.

Abnormal color vision

adrenomyeloneuropathy

AMN

ALD


Input: Furthermore, rearrangements of the color vision gene cluster were found in four of eight ALD kindreds.

ALD


Input: This led us to propose that a single DNA rearrangement could underlie both ALD and abnormal color vision in these patients.

ALD

abnormal color vision


Input: Study of 34 French ALD patients failed to reveal a higher than expected frequency of green/red visual pigment rearrangements 3 to the red/green color vision gene complex.

ALD


Input: The previous report of such rearrangements was based on small numbers and lack of knowledge that the frequency of " abnormal " color vision arrays on molecular analysis was twice as high as expected on the basis of the frequency of phenotypic color vision defects.

phenotypic color vision defects


Input: The red/green color pigment (R/GCP) region was studied by pulsed-field gel electrophoresis in 14 of these patients, and we did not find any fragment size difference between the patients and normal individuals who have the same number of pigment genes.


Input: The R/GCP region was also analyzed in 29 French and seven North American ALD patients by using six genomic DNA probes, isolated from a cosmid walk, that flank the color vision genes.

ALD


Input: No deletions were found with probes that lie 3 of the green pigment genes.


Input: One of the eight previously reported ALD individuals has a long deletion 5 of the red pigment gene, a deletion causing blue cone monochromacy.

ALD


Input: This finding and the previous findings of a 45% frequency of phenotypic color vision defects in patients with AMN may suggest that the ALD/AMN gene lies 5 to the red pigment gene and that the frequent phenotypic color vision anomalies owe their origin to deleted DNA that includes regulatory genes for color vision.

AMN

ALD

AMN

color vision anomalies


Input: It is possible, however, that phenotypic color vision anomalies in AMN may be phenocopies secondary to retinal or neural involvement by the disease.

color vision anomalies

AMN


Input: The single case of blue cone monochromacy may therefore be a fortuitous coincidence of two diseases..


Input: Paroxysmal nocturnal haemoglobinuria with coexisting deficiency of the ninth component of complement: lack of massive haemolytic attack.

Paroxysmal nocturnal haemoglobinuria

deficiency of the ninth component of complement

haemolytic attack


Input: A 47-year-old woman with paroxysmal nocturnal haemoglobinuria (PNH) was found to have an inherited deficiency in the ninth complement component (C9).

paroxysmal nocturnal haemoglobinuria

PNH

inherited deficiency in the ninth complement component


Input: In complement-sensitivity lysis tests, 80% of her erythrocytes were markedly complement-sensitive (PNH-III).


Input: Laser cytofluorimetry with a monoclonal antibody against decay-accelerating factor (DAF) revealed that 95% of her erythrocytes were DAF-negative.


Input: Surprisingly, she has suffered only mild haemolysis and has never experienced massive spontaneous haemolysis.

haemolysis

haemolysis


Input: Gross haemoglobinuria and jaundice occurred only after receiving postoperative transfusion of whole blood.

haemoglobinuria

jaundice


Input: In her serum, C9 was not detectable either by immunological or by functional assays.


Input: Both the Ham test and the sugar water test using normal human serum or plasma yielded marked haemolysis of the patients erythrocytes.


Input: When the patients serum or plasma was used, only a trace of lysis was detected.


Input: Addition of purified human C9 to her plasma fully restored haemolysis.


Input: These observations indicated that C9 may play a critical role in haemolytic attacks in patients with PNH and that characteristic haemolysis in PNH may be tempered by coexisting C9 deficiency..

haemolytic attacks

PNH

haemolysis

PNH

C9 deficiency


Input: Duplicational mutation at the Duchenne muscular dystrophy locus: its frequency, distribution, origin, and phenotypegenotype correlation.

Duchenne muscular dystrophy


Input: Partial gene deletion is the major cause of mutation leading to Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

Duchenne muscular dystrophy

DMD

Becker muscular dystrophy

BMD


Input: Partial gene duplication has also been recognized in a few cases.


Input: We have conducted a survey for duplication in 72 unrelated nondeletion patients, analyzed by Southern blot hybridization with clones representing the entire DMD cDNA.

DMD


Input: With careful quantitative analysis of hybridization band intensity, 10 cases were found to carry a duplication of part of the gene, a frequency of 14% for nondeletion cases (10/72), or 6% for all cases (10/181).


Input: The extent of these duplications has been characterized according to the published exon-containing HindIII fragment map, and in six of the 10 duplications a novel restriction fragment that spanned the duplication junction was detected.


Input: The resulting translational reading frame of mRNA has been predicted for nine duplications.


Input: A shift of the reading frame was predicted in four of the six DMD cases and in one of the two intermediate cases, while the reading frame remained uninterrupted in both BMD cases.

DMD

BMD


Input: RFLP and quantitative Southern blot analyses revealed a grandpaternal origin of duplication in four families and grandmaternal origin in one family.


Input: In all five families, the duplication was found to originate from a single X chromosome.


Input: Unequal sister-chromatid exchange is proposed to be the mechanism for the formation of these duplications..


Input: Glucose 6-phosphate dehydrogenase variants: Gd (+) Alexandra associated with neonatal jaundice and Gd (-) Camperdown in a young man with lamellar cataracts.

neonatal jaundice

lamellar cataracts


Input: Two male subjects are described, with unusual clinical presentations and with hitherto undescribed G6PD variants.


Input: The first, of Italian extraction, suffered from severe neonatal jaundice following maternal ingestion of fresh broad beans (Vicia fava) both prenatally and postnatally the expression of the enzymatic defect was much more severe in the neonatal period than on retesting in adolescence, when biochemical characterization showed unique features which justify designation as a new variant Gd (+) Alexandra.

neonatal jaundice


Input: The second patient, a boy of Maltese extraction who was found to have bilateral lamellar cataracts at the age of 4 years, was identified as G6PD deficient only as a result of a survey of children of Mediterranean origin with unexplained cataract formation; he has approximately 15% of normal enzyme activity, with another unique combination of biochemical characteristics which has led to its designation as Gd (-) Camperdown.

bilateral lamellar cataracts

G6PD deficient

cataract


Input: Although this association may be coincidental, it prompts further attention to the possibility that under certain circumstances G6PD deficiency may favor cataract formation.

G6PD deficiency

cataract


Input: The two cases illustrate the value of characterization of the mutant enzyme whenever unexpected clinical or laboratory results are obtained..


Input: Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma.

von Hippel-Lindau disease

sporadic cerebellar haemangioblastoma

renal cell carcinoma


Input: Analysis of the age incidence curves for unilateral and bilateral retinoblastoma led Knudson to propose that hereditary tumours may arise by a single event and sporadic tumours by a two stage mutation process.

unilateral and bilateral retinoblastoma

hereditary tumours

sporadic tumours


Input: It has been suggested recently that sporadic renal cell carcinoma may arise from a two stage mutation process.

sporadic renal cell carcinoma


Input: We analysed the age incidence curves for symptomatic renal cell carcinoma (n = 26) and cerebellar haemangioblastoma (n = 68) in 109 patients with von Hippel-Lindau (VHL) disease, and compared them to 104 patients with sporadic renal cell carcinoma and 43 patients with sporadic cerebellar haemangioblastoma.

renal cell carcinoma

cerebellar haemangioblastoma

von Hippel-Lindau (VHL) disease

sporadic renal cell carcinoma

sporadic cerebellar haemangioblastoma


Input: The age incidence curves for renal cell carcinoma and cerebellar haemangioblastoma in VHL disease were compatible with a single mutation model, whereas the age incidence curves for sporadic renal cell carcinoma and cerebellar haemangioblastoma suggested a two stage mutation process.

renal cell carcinoma

cerebellar haemangioblastoma

VHL disease

sporadic renal cell carcinoma

cerebellar haemangioblastoma


Input: These data are compatible with the VHL gene functioning as a recessive tumour suppressor gene.

VHL

tumour


Input: Sporadic cerebellar haemangioblastoma and some renal cell carcinoma may arise from somatic mutations inactivating both alleles at the VHL locus..

Sporadic cerebellar haemangioblastoma

renal cell carcinoma

VHL


Input: Screening for carriers of Tay-Sachs disease among Ashkenazi Jews.

Tay-Sachs disease


Input: A comparison of DNA-based and enzyme-based tests.


Input: BACKGROUND AND METHODS.


Input: The prevention of Tay-Sachs disease (GM2 gangliosidosis, type 1) depends on the identification of carriers of the gene for this autosomal recessive disorder.

Tay-Sachs disease

GM2 gangliosidosis, type 1

autosomal recessive disorder


Input: We compared the enzyme-based test widely used in screening for Tay-Sachs disease with a test based on analysis of DNA.

Tay-Sachs disease


Input: We developed methods to detect the three mutations in the HEXA gene that occur with high frequency among Ashkenazi Jews two mutations cause infantile Tay-Sachs disease, and the third causes the adult-onset form of the disease.

Tay-Sachs disease


Input: DNA segments containing these mutation sites were amplified with the polymerase chain reaction and analyzed for the presence of the mutations.


Input: RESULTS.


Input: Among 62 Ashkenazi obligate carriers of Tay-Sachs disease, the three specific mutations accounted for all but one of the mutant alleles (98 percent).

Tay-Sachs disease


Input: In 216 Ashkenazi carriers identified by the enzyme test, DNA analysis showed that 177 (82 percent) had one of the identified mutations.


Input: Of the 177, 79 percent had the exon 11 insertion mutation, 18 percent had the intron 12 splice-junction mutation, and 3 percent had the less severe exon 7 mutation associated with adult-onset disease.


Input: The results of the enzyme tests in the 39 subjects (18 percent) who were defined as carriers but in whom DNA analysis did not identify a mutant allele were probably false positive (although there remains some possibility of unidentified mutations).


Input: In addition, of 152 persons defined as noncarriers by the enzyme-based test, 1 was identified as a carrier by DNA analysis (i. e e., a false negative enzyme-test result).


Input: CONCLUSIONS.


Input: The increased specificity and predictive value of the DNA-based test make it a useful adjunct to the diagnostic tests currently used to screen for carriers of Tay-Sachs disease.

Tay-Sachs disease


Input: Total deficiency of plasma cholesteryl ester transfer protein in subjects homozygous and heterozygous for the intron 14 splicing defect.

Total deficiency of plasma cholesteryl ester transfer protein


Input: The molecular basis of cholesteryl ester transfer protein (CETP) deficiency was investigated in 4 unrelated CETP-deficient families.

cholesteryl ester transfer protein (CETP) deficiency

CETP-deficient


Input: The high density lipoprotein-cholesterol levels of the probands exceeded 150 mg/dl.


Input: The plasma of the probands was totally deficient in CETP activity and mass.


Input: The genomic DNA of the patients was amplified by polymerase chain reaction, using two oligonucleotide primers located in the intron 12 and 14 of the CETP gene, and the amplified products were directly sequenced.


Input: Two patients were homozygous for a G-to-A change at the 5-splice donor site of the intron 14.


Input: The G-to-A change would cause impaired splicing of pre-messenger RNA.


Input: The other two probands were heterozygous for the mutation, but totally lacked CETP.


Input: Their lipoprotein patterns were also similar to those of the two homozygotes.


Input: Thus, other genetic defects or metabolic factors influencing CETP expression are implicated.

genetic defects


Input: The data suggest that the G-to-A mutation may be common in human plasma CETP deficiency.

CETP deficiency


Input: Furthermore, there could be compound heterozygotes who totally lack plasma CETP and have lipoprotein profiles similar to those of homozygotes..


Input: Molecular genetics of the glucose-6-phosphate dehydrogenase (G6PD) Mediterranean variant and description of a new G6PD mutant, G6PD Andalus1361A.


Input: Glucose-6-phosphate dehydrogenase (G6PD; E. C. 1. 1. 1. 49) deficiency is the most common human enzymopathy; more than 300 different biochemical variants of the enzyme have been described.

Glucose-6-phosphate dehydrogenase (G6PD; E. C. 1. 1. 1. 49) deficiency

enzymopathy


Input: In many parts of the world the Mediterranean type of G6PD deficiency is prevalent.

G6PD deficiency


Input: However, G6PD Mediterranean has come to be regarded as a generic term applied to similar G6PD mutations thought, however, to represent a somewhat heterogeneous group.


Input: A C----T mutation at nucleotide 563 of G6PD Mediterranean has been identified by Vulliamy et al., and the same mutation has been found by De Vita et al. in G6PD Mediterranean, G6PD Sassari, and G6PD Cagliari.


Input: The latter subjects had an additional mutation, at nucleotide 1311, that did not produce a coding change.


Input: We have examined genomic DNA of five patients--four of Spanish origin and one of Jewish origin--having enzymatically documented G6PD Mediterranean.


Input: All had both the mutation at nucleotide 563 and that at nucleotide 1311.


Input: A sixth sample, resembling G6PD Mediterranean kinetically but with a slightly rapid electrophoretic mobility, was designated G6PD Andalus and was found to have a different mutation, a G----A transition at nucleotide 1361, producing an arginine-to-histidine substitution.


Input: These studies suggest that G6PD Mediterranean is, after all, relatively homogeneous.


Input: A normal male with an inherited deletion of one exon within the DMD gene.

DMD


Input: We describe two brothers with identical inherited deletions of one single exon within the middle of the DMD gene; one brother has Becker muscular dystrophy diagnosed at 11 years of age, whereas the older brother is normal at 18.

DMD

Becker muscular dystrophy


Input: These results have implications for genetic counselling and prenatal diagnosis in families with Becker muscular dystrophy..

Becker muscular dystrophy


Input: Duchenne muscular dystrophy gene expression in normal and diseased human muscle.

Duchenne muscular dystrophy


Input: A probe for the 5 end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD.

Duchenne muscular dystrophy

DMD

DMD


Input: Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion.


Input: In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers..

DMD


Input: Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene.

Duchenne muscular dystrophy

DMD


Input: Eighty unrelated individuals with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus.

Duchenne muscular dystrophy

DMD

Becker muscular dystrophy

BMD

DMD


Input: This region includes the last five exons detected by cDNA5b-7, all exons detected by cDNA8, and the first two exons detected by cDNA9.


Input: These 80 individuals account for approximately 75% of 109 deletions of the gene, detected among 181 patients analyzed with the entire dystrophin cDNA.


Input: Endpoints for many of these deletions were further characterized using two genomic probes, p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper).


Input: Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype.


Input: Thirty-eight independent patients were old enough to be classified as DMD, BMD, or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries.

DMD

BMD


Input: Of these, eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact, while 21 DMD patients, 7 intermediate patients, and 1 BMD patient had gene deletions predicted to disrupt the reading frame.

BMD

DMD

BMD


Input: Thus, with two exceptions, frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions.


Input: This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings, by Malhotra et al. at the 5' end of the gene.


Input: Cloning of breakpoints of a chromosome translocation identifies the AN2 locus.


Input: Chromosome translocations involving 11p13 have been associated with familial aniridia in two kindreds highlighting the chromosomal localization of the AN2 locus.

familial aniridia


Input: This locus is also part of the WAGR complex (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation).

WAGR

Wilms tumor

aniridia

genitourinary abnormalities

mental retardation


Input: In one kindred, the translocation is associated with a deletion, and probes for this region were used to identify and clone the breakpoints of the translocation in the second kindred.


Input: Comparison of phage restriction maps exclude the presence of any sizable deletion in this case.


Input: Sequences at the chromosome 11 breakpoint are conserved in multiple species, suggesting that the translocation falls within the AN2 gene..


Input: Linkage analysis of the apolipoprotein C2 gene and myotonic dystrophy on human chromosome 19 reveals linkage disequilibrium in a French-Canadian population.

myotonic dystrophy


Input: The gene for human apolipoprotein C2 (APOC2), situated on the proximal long arm of chromosome 19, is closely linked to the gene for the most common form of adult muscular dystrophy, myotonic dystrophy (DM).

muscular dystrophy

myotonic dystrophy

DM


Input: Six APOC2 RFLPs (TaqI, BglI, BanI, BamHI, NcoI, and AvaII) have been identified to date.


Input: We have conducted a comprehensive DM linkage study utilizing all six RFLPs and involving 50 families and 372 individuals.

DM


Input: The most informative RFLPs are, in descending order, NcoI (lod = 6. 64, theta = 0. 05), BglI (lod = 6. 12, theta = 0. 05), AvaII (lod = 6. 02, theta = 0. 03), BanI (lod = 5. 76, theta = 0. 04), TaqI (lod = 4. 29, theta = 0. 06), and BamHI (lod = 1. 75, theta = 0. 01).


Input: A substantial increase in the lod scores over those seen with the individual RFLPs was obtained when the linkage of the entire APOC2 haplotype (composed of the six RFLPs) was studied (lod = 17. 87, theta = 0. 04).


Input: We have observed significant inter-APOC2 RFLP linkage disequilibrium.


Input: Consequently, the three most informative RFLPs have been found to be BanI, TaqI, and either BglI, AvaII, or NcoI polymorphisms.


Input: We also demonstrate linkage disequilibrium between DM and APOC2 in our French-Canadian population (standardized disequilibrium constant phi =. 22, chi 2 = 5. 12, df = 1, P less than 0. 04).


Input: This represents the first evidence of linkage disequilibrium between APOC2 and the DM locus.

DM


Input: Phenylalanine hydroxylase gene haplotypes in Polynesians: evolutionary origins and absence of alleles associated with severe phenylketonuria.

phenylketonuria


Input: A total of 630 haplotypes for the phenylalanine hydroxylase (PAH) gene locus were established in five groups of Polynesians comprising Samoans, Tongans, Cook Islanders, Maori, and Niueans.


Input: Considerable genetic continuity was demonstrated between these widely dispersed populations, since three common haplotypes (4, 1, and 7) constituted over 95% of alleles.


Input: A control group of individuals from Southeast Asia shared the same major haplotypes, 4, 1, and 7, with Polynesians.


Input: These data provide further support for the theories of genetic homogeneity and of Asian affinities of the Polynesian precursor populations.


Input: The absence of severe phenylketonuria (PKU) in both Polynesians and Southeast Asians is consistent with the lack of PAH haplotypes 2 and 3, on which the severe PKU mutants have arisen among Caucasians..

phenylketonuria

PKU

PKU


Input: Preferential germline mutation of the paternal allele in retinoblastoma.

retinoblastoma


Input: The event triggering malignant proliferation in 70% of retinoblastoma tumours is loss of heterozygosity for chromosome 13q14, whereby the normal retinoblastoma gene (RB1) allele is lost and an already mutated RB1 allele remains in the tumour.

retinoblastoma tumours

retinoblastoma

tumour


Input: The first allele suffers a mutational event--deletion, duplication or point mutation (manuscript in preparation)--either in the germ line (all bilateral patients) or in a somatic retinal cell (most unilateral patients).


Input: Most bilateral patients have no family history of retinoblastoma and are presumed to have new germline mutations which arose in the egg, sperm or early embryo.

retinoblastoma


Input: We have determined the parental origin of the retained allele in nine retinoblastoma tumours from eight unrelated non-familial cases by using RB1-linked genetic markers.

retinoblastoma tumours


Input: Six tumours retained the paternal allele and three retained the maternal allele.

tumours


Input: Of the three unilateral tumours, only one retained the paternal RB1 allele.

unilateral tumours


Input: Thus, there is no evidence that the paternal RB1 allele is preferentially retained in retinoblastoma, as has been suggested to be the case in osteosarcoma.

retinoblastoma

osteosarcoma


Input: By contrast, tumours from four of the five bilateral patients retained the paternal RB1 allele.

tumours


Input: This suggests either that new germline RB1 mutations arise more frequently during spermatogenesis than during oogenesis, or that imprinting in the early embryo affects chromosomal susceptibility to mutation..


Input: Haplotype analysis of the phenylalanine hydroxylase gene in Turkish phenylketonuria families.

phenylketonuria


Input: We have estimated the haplotype distribution of mutant and normal phenylalanine hydroxylase (PAH) alleles for 17 Turkish phenylketonuria (PKU) families 20 normal and 27 mutated PAH alleles could be identified.

phenylketonuria

PKU


Input: Of the latter, the most prevalent were associated with haplotype 6 (29. 6%), 1 (18. 5%) and 36 (11. 1%), while the normal alleles were preferentially associated with haplotype 1 (20%).


Input: Of the 19 different haplotypes observed, 5 have not been described previously.


Input: The haplotype distribution differed significantly from that of the Northern European population.


Input: Two of the eight polymorphic sites were in association with PKU.

PKU


Input: No deletions of exon sequences were found in the families analysed.


Input: Huntington disease: no evidence for locus heterogeneity.

Huntington disease


Input: A total of 63 families with Huntington disease (HD) were examined for linkage between HD and G8 (D4S10).

Huntington disease

HD

HD


Input: The families included 57 Caucasian, four Black American, and two Japanese.


Input: The combined maximum lod score was 87.


Input: 69 at theta = 0.


Input: 04 (99% confidence interval 0. 018-0. 071).


Input: The maximum frequency of recombination was 0.


Input: 03 in males and 0.


Input: 05 in females.


Input: Fifty-seven families gave positive lod scores; five small families gave mildly negative lod scores.


Input: The maximum likelihood estimate of alpha, the proportion of linked loci, was 1.


Input: 0 with a lower 99% confidence interval of 0.


Input: These data suggest that there is only one HD locus, although a second rare locus cannot be ruled out.

HD


Input: Haplotype and multipoint linkage analysis in Finnish choroideremia families.

choroideremia


Input: Multipoint linkage analysis of choroideremia (TCD) and seven X chromosomal restriction fragment length polymorphisms (RFLPs) was carried out in 18 Finnish TCD families.

choroideremia

TCD

TCD


Input: The data place TCD distal to PGK and DXS72, very close to DXYS1 and DXYS5 (Zmax = 24 at theta = 0) and proximal to DXYS4 and DXYS12.

TCD


Input: This agrees with the data obtained from other linkage studies and from physical mapping.


Input: All the TCD males and carrier females studied have the same DXYS1 allele in coupling with TCD.

TCD

TCD


Input: In Northeastern Finland, 66/69 chromosomes carrying TCD had the same haplotype at loci DXS72, DXYS1, DXYS4, and DXYS12.

TCD


Input: The same haplotype is seen in only 15/99 chromosomes not carrying TCD.

TCD


Input: Moreover, in 71/104 non-TCD chromosomes, the haplotype at six marker loci is different from those seen in any of the 76 TCD chromosomes.

TCD


Input: This supports the previously described hypothesis that the large Northern Finnish choroideremia pedigrees, comprising a total of over 80 living patients representing more than a fifth of all TCD patients described worldwide, carry the same mutation.

choroideremia

TCD


Input: These linkage and haplotype data provide improved opportunities for prenatal diagnosis based on RFLP studies..


Input: Autosomal dominant aniridia linked to the chromosome 11p13 markers catalase and D11S151 in a large Dutch family.

aniridia


Input: In a large pedigree with autosomal dominant aniridia, we found close linkage between the aniridia locus AN2 and the markers catalase (CAT) (zeta = 7. 27 at theta = 0. 00) and D11S151 (zeta = 3. 86 at theta = 0. 10) flanking the AN2 locus on 11p13.

aniridia

aniridia


Input: Positive lod scores were also obtained for the 11p13----11p14 markers D11S16 and FSHB with the linkage group CAT/AN2/D11S151.


Input: We conclude that the autosomal dominant aniridia in this family is due to a mutation at the AN2 locus on 11p13.

aniridia


Input: We have excluded linkage (zeta less than-2 at theta less than 0. 18) between the aniridia and the chromosome 2p25 marker D2S1 (linked to ACP1).

aniridia


Input: Recombination events that locate myotonic dystrophy distal to APOC2 on 19q.

myotonic dystrophy


Input: We previously reported a recombination in an individual with myotonic dystrophy (DM) which placed the markers D19S19 and APOC2 on the same side of the DM locus.

myotonic dystrophy

DM

DM


Input: Haplotyping of this family with more recently characterized probes which are either tightly linked to DM or distal to the linkage group at q13.

DM


Input: 2 shows that the DM locus is distal to APOC2.

DM


Input: This is confirmed by other recombinants where DM segregates with distal probes.

DM


Input: Additional marker to marker recombinations in unaffected individuals are reported and support the order and orientation of the DM linkage group as pter-(INSR, LDLR, S9)-(S19, BCL3, APOC2)-(CKMM, DM)-(S22, + + + PRKCG)-qter.

DM


Input: The data presented here cannot determine whether DM is proximal or distal to CKMM.

DM


Input: The consequences of this probe order for antenatal diagnosis and future research aiming to isolate the gene which is affected in DM are discussed.

DM


Input: Mutations in the RB1 gene and their effects on transcription.


Input: Inactivation of both alleles of the RB1 gene during normal retinal development initiates the formation of a retinoblastoma (RB) tumor.

retinoblastoma (RB) tumor


Input: To identify the mutations which inactivate RB1, 21 RB tumors isolated from 19 patients were analyzed with the polymerase chain reaction or an RNase protection assay or both.

RB tumors


Input: Mutations were identified in 13 of 21 RB tumors; in 8 tumors, the precise errors in nucleotide sequence were characterized.

RB tumors

tumors


Input: Each of four germ line mutations involved a small deletion or duplication, while three somatic mutations were point mutations leading to splice alterations and loss of an exon from the mature RB1 mRNA.


Input: We were unable to detect expression of the mutant allele in lymphoblasts of three bilaterally affected patients, although the mutation was present in the genomic DNA and transcripts containing the mutations were obvious in the RB tumors in the absence of a normal RB1 allele.

RB tumors


Input: The variations in the level of expression of mutant transcripts suggest deregulation of RB1 transcription in the absence of a functional RB1 gene product..


Input: Partial deletion 8q without Langer-Giedion syndrome: a recognisable syndrome.

Langer-Giedion syndrome


Input: We report two de novo cases of del (8) (pter----q24. 1) with breakpoints involving the distal part of band 8q24.


Input: 1 1.


Input: The clinical features were similar and there were no obvious stigmata of Langer-Giedion syndrome (LGS).

Langer-Giedion syndrome

LGS


Input: There are three other cases reported with a deletion of chromosome 8 at approximately the same breakpoint, one without LGS and some similarities to our cases, the other two with LGS.

LGS

LGS


Input: Our findings would support the observation that the critical segment for the assignment of LGS is proximal to or involves the proximal part of 8q24.

LGS


Input: 1, but a review of published reports suggests that the aetiology of LGS may be a more complex issue

LGS


Input: Myotonic dystrophy is closely linked to the gene for muscle-type creatine kinase (CKMM).

Myotonic dystrophy


Input: We have studied genetic linkage between the gene for creatine kinase muscle type (CKMM) and the gene for myotonic dystrophy (DM).

myotonic dystrophy

DM


Input: In a panel of 65 myotonic dystrophy families from Canada and the Netherlands, a maximum lod score (Zmax) of 22.

myotonic dystrophy


Input: 8 at a recombination frequency (theta) of 0.


Input: 03 was obtained.


Input: Tight linkage was also demonstrated for CKMM and the gene for apolipoprotein C2 (ApoC2).


Input: This establishes CKMM as a useful marker for myotonic dystrophy


Input: Color vision defects in adrenomyeloneuropathy.

Color vision defects

adrenomyeloneuropathy


Input: The relationship between abnormal color vision and adrenomyeloneuropathy (AMN) was investigated in 27 AMN patients and 31 age-matched controls by using the Farnsworth-Munsell 100 Hue test.

abnormal color vision

adrenomyeloneuropathy

AMN

AMN


Input: Twelve (44%) of 27 patients showed test scores significantly above normal.


Input: The axes of bipolarity determined by the testing differed widely between the patients with abnormal scores, compatible with the notion that different alterations in visual pigment genes occur in different AMN kindreds.

AMN


Input: These observations confirm our earlier impression that the frequency of abnormal color vision is increased in these kindreds, and it supports our contentions that (1) AMN (and its companion, adrenoleukodystrophy) are very closely linked to the visual pigment loci at Xq28 and (2) this proximity might provide the opportunity to observe contiguous gene defects..

abnormal color vision

AMN

adrenoleukodystrophy

contiguous gene defects


Input: Molecular analysis of a female Lesch-Nyhan patient.

Lesch-Nyhan


Input: We report the identification of a female patient with the X-linked recessive Lesch-Nyhan syndrome (hypoxanthine phosphoribosyltransferase [HPRT] deficiency).

Lesch-Nyhan syndrome

hypoxanthine phosphoribosyltransferase [HPRT] deficiency


Input: Cytogenetic and carrier studies revealed structurally normal chromosomes for this patient and her parents and demonstrated that this mutation arose through a de novo gametic event.


Input: Comparison of this patients DNA with the DNA of her parents revealed that a microdeletion, which occurred within a maternal gamete and involved the entire HPRT gene, was partially responsible for the disease in this patient.


Input: Somatic cell hybrids, generated to separate maternal and paternal X chromosomes, showed that expression of two additional X-linked enzymes, phosphoglycerate kinase and glucose-6-phosphate dehydrogenase, were expressed only in cells that contained the maternal X chromosome, suggesting the presence of a functionally inactive paternal X chromosome.


Input: Furthermore, comparison of methylation patterns within a region of the HPRT gene known to be important in gene regulation revealed differences between DNA from the father and the patient, in keeping with an active HPRT locus in the father and an inactive HPRT locus in the patient.


Input: Together these data indicate that nonrandom inactivation of the cytogenetically normal paternal X chromosome and a microdeletion of the HPRT gene on an active maternal X chromosome were responsible for the absence of HPRT in this patient..


Input: Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein.

Pelizaeus-Merzbacher disease

X-linked neurologic disorder of myelin metabolism


Input: The nosology of the inborn errors of myelin metabolism has been stymied by the lack of molecular genetic analysis.

inborn errors of myelin metabolism


Input: Historically, Pelizaeus-Merzbacher disease has encompassed a host of neurologic disorders that present with a deficit of myelin, the membrane elaborated by glial cells that encircles and successively enwraps axons.

Pelizaeus-Merzbacher disease

neurologic disorders

deficit of myelin


Input: We describe here a Pelizaeus-Merzbacher pedigree of the classical type, with X-linked inheritance, a typical clinical progression, and a pathologic loss of myelinating cells and myelin in the central nervous system.

Pelizaeus-Merzbacher


Input: To discriminate variants of Pelizaeus-Merzbacher disease, a set of oligonucleotide primers was constructed to polymerase-chain-reaction (PCR) amplify and sequence the gene encoding proteolipid protein (PLP), a structural protein that comprises half of the protein of the myelin sheath.

Pelizaeus-Merzbacher disease


Input: The PLP gene in one of two affected males and the carrier mother of this family exhibited a single base difference in the more than 2 kb of the PLP gene sequenced, a C----T transition that would create a serine substitution for proline at the carboxy end of the protein.


Input: Our results delineate the clinical features of Pelizaeus-Merzbacher disease, define the possible molecular pathology of this dysmyelinating disorder, and address the molecular classification of inborn errors of myelin metabolism.

Pelizaeus-Merzbacher disease

dysmyelinating disorder

inborn errors of myelin metabolism


Input: Patients with the classical form (type I) and the more severely affected, connatal variant of Pelizaeus-Merzbacher disease (type II) would be predicted to display mutation at the PLP locus.

Pelizaeus-Merzbacher disease (type II)


Input: The other variants (types III-VI), which have sometimes been categorized as Pelizaeus-Merzbacher disease, may represent mutations in genes encoding other structural myelin proteins or proteins critical to myelination..

Pelizaeus-Merzbacher disease


Input: Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA.

von Willebrand disease

von Willebrand


Input: von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, can result from either a quantitative or a qualitative defect in the adhesive glycoprotein, von Willebrand factor (vWF).

von Willebrand disease

vWD

inherited bleeding disorder

von Willebrand


Input: Molecular studies of vWD have been limited by the large size of the vWF gene and difficulty in obtaining the vWF mRNA from patients.

vWD


Input: By use of an adaptation of the polymerase chain reaction, vWF mRNA was amplified and sequenced from peripheral blood platelets.


Input: A silent vWF allele was identified, resulting from a cis defect in vWF mRNA transcription or processing.


Input: In two type IIA vWD patients, two different but adjacent missense mutations were identified, the locations of which may identify an important vWF functional domain.

type IIA vWD


Input: Expression in heterologous cells of recombinant vWF containing one of these latter mutations reproduced the characteristic structural abnormality seen in type IIA vWD plasma..

type IIA vWD


Input: Familial deficiency of the seventh component of complement associated with recurrent meningococcal infections.

Familial deficiency of the seventh component of complement

meningococcal infections


Input: We describe an 11-year-old girl suffering from recurrent meningitis with a complete absence of the seventh component of complement (C7).

recurrent meningitis

absence of the seventh component of complement


Input: Diagnosis was established by haemolytic titration and western blotting.


Input: The patients serum lacked the 85 kDa C7 chain.


Input: Haemolytic activity of serum was reconstituted with either pooled normal human serum or with purified C7.


Input: The relatives (parents and one sister) had half-normal levels of both immunochemically and functionally determined C7, indicating a heterozygous state for C7 deficiency..

C7 deficiency


Input: Translocation t (5; 11) (q13. 1; p13) associated with familial isolated aniridia.

isolated aniridia


Input: A father and daughter with isolated aniridia were observed to have an apparently balanced, reciprocal translocation involving chromosomes 5 and 11 [t (5; 11) (q13. 1; p13)].

isolated aniridia


Input: No other clinical characteristics often associated with the deletion of 11p13 were observed in this family.


Input: This finding, in association with 3 other instances of single breaks at 11p13 and aniridia, supports the assignment of AN2 to 11p13.

aniridia


Input: Homozygous hypobetalipoproteinemia: a disease distinct from abetalipoproproteinemia at the molecular level.

Homozygous hypobetalipoproteinemia

abetalipoproproteinemia


Input: apoB DNA, RNA, and protein from two patients with homozygous hypobetalipoproteinemia (HBL) were evaluated and compared with normal individuals.

homozygous hypobetalipoproteinemia

HBL


Input: Southern blot analysis with 10 different cDNA probes revealed a normal gene without major insertions, deletions, or rearrangements.


Input: Northern and slot blot analyses of total liver mRNA from HBL patients documented a normal size apoB mRNA that was present in greatly reduced quantities.

HBL


Input: ApoB protein was detected within HBL hepatocytes utilizing immunohistochemical techniques; however, it was markedly reduced in quantity when compared with control samples.

HBL


Input: No apoB was detectable in the plasma of HBL individuals with an ELISA assay.

HBL


Input: These data are most consistent with a mutation in the coding portion of the apoB gene in HBL patients, leading to an abnormal apoB protein and apoB mRNA instability.

HBL


Input: These results are distinct from those previously noted in abetalipoproteinemia, which was characterized by an elevated level of hepatic apoB mRNA and accumulation of intracellular hepatic apoB protein..

abetalipoproteinemia


Input: Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement.

Lesch-Nyhan


Input: Molecular analysis of an unusual patient with the Lesch-Nyhan syndrome has suggested that the mutation is due to a partial HPRT gene duplication.

Lesch-Nyhan syndrome


Input: We now report the cloning and sequencing of the mutant HPRT cDNA which shows the precise duplication of exons 2 and 3.


Input: This mutation is the result of an internal duplication of 16-20 kilobases of the gene.


Input: The structure of the mutant gene suggests that the duplication was not generated by a single unequal crossing-over event between two normal HPRT alleles.


Input: Growth of Epstein-Barr virus-transformed lymphoblasts from this patient in selective medium has permitted isolation of spontaneous HPRT + revertants of this mutation.

Epstein-Barr


Input: The reversion event involves a second major HPRT gene rearrangement where most or all of the duplicated portion of the mutant gene is deleted.


Input: The original mutation therefore has the potential for spontaneous somatic reversion.


Input: This may explain the relatively mild symptoms of the Lesch-Nyhan syndrome exhibited by this patient..

Lesch-Nyhan syndrome


Input: Complex glycerol kinase deficiency: molecular-genetic, cytogenetic, and clinical studies of five Japanese patients.

Complex glycerol kinase deficiency


Input: Five male Japanese patients with complex glycerol kinase deficiency (CGKD) and their relatives were studied clinically, cytogenetically, and molecular-genetically.

complex glycerol kinase deficiency

CGKD


Input: All patients had muscular dystrophy or muscle weakness, mental retardation, congenital adrenal hypoplasia, and glycerol kinase deficiency.

muscular dystrophy

muscle weakness

mental retardation

congenital adrenal hypoplasia

glycerol kinase deficiency


Input: High-resolution GTG-banded chromosomes showed a microdeletion in the Xp21 region in all four patients examined and in all five mothers.


Input: Southern hybridizations, after digestions by restriction endonucleases, with various cloned DNAs (D2, 99-6, B24, C7, L1-4, cDMD13-14, J66-HI, P20, J-Bir, ERT87-30, ERT87-15, ERT87-8, ERT87-1, XJ-1. 1, 754, cx5. 7, and OTC-1) that are located around Xp21 also showed a deletion in the genome of all patients and mothers.


Input: Although the deletion differed in size among patients, a segment commonly absent was located between the genomic sequences corresponding to L1-4 and cDMD13-14.


Input: This finding indicated that the gene coding for glycerol kinase (GK) is located within this segment.


Input: A comparison of the clinical manifestations of the present five patients and reported CGKD or Duchenne muscular dystrophy (DMD) patients with DNA deletion suggests the existence of a certain gene responsible for gonadotropin deficiency (GTD).

CGKD

Duchenne muscular dystrophy

DMD

gonadotropin deficiency

GTD


Input: The result of the present study and results of previous studies suggest that genes for ornithine transcarbamylase (OTC), DMD, and GK and putative genes responsible for congenital adrenal hypoplasia (AHC) and GTD are arranged from telomere to centromere as pter--GTD--AHC--GK--DMD--OTC--cen

DMD

congenital adrenal hypoplasia

AHC

GTD


Input: Genetically determined low C4: a predisposing factor to autoimmune chronic active hepatitis.

autoimmune chronic active hepatitis


Input: Of 26 patients with autoimmune chronic active hepatitis (CAH) starting in childhood 18 (69%) had low C4 and 5 (19%) had low C3 serum levels.

autoimmune chronic active hepatitis

CAH


Input: Impaired hepatic synthesis and immune-consumption were unlikely since transferrin levels were normal in all patients, albumin levels were persistently low in only 3, and only 3 had raised levels of activation fragment C3d.


Input: C4d was normal in all patients studied.


Input: In the families of 12 probands with low C4, 7 parents had low C4 and 2 had levels which were at the lower limit of normal.


Input: 5 of 10 siblings from 5 families had low C4.


Input: These results suggest that low C4 levels in CAH are genetically determined.

CAH


Input: C4 phenotyping in 20 patients and in 26 parents showed that 90% and 81%, respectively, had null allotypes at either the C4A or C4B locus compared with 59% in controls, indicating that defective expression of structural genes may contribute to the observed C4 deficiency..

C4 deficiency


Input: An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2.

phenylketonuria


Input: Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH, phenylalanine 4-monooxygenase, EC 1. 14. 16. 1).

Phenylketonuria

PKU

autosomal recessive human genetic disorder

deficiency of hepatic phenylalanine hydroxylase


Input: PKU is a common inborn error of amino-acid metabolism in caucasian populations and approximately 1 in 50 individuals are carriers of a PKU allele.

PKU

inborn error of amino-acid metabolism

PKU


Input: To define the molecular basis of PKU, we characterized twelve restriction fragment-length polymorphism (RFLP) haplotypes of the PAH locus in the northern European population and observed that 90% of the PKU alleles in this population are confined to four common RFLP haplotypes.

PKU

PKU


Input: We have recently reported a splicing mutation in the PAH gene that is associated with RFLP haplotype 3 which is present at about 40% of mutant alleles.


Input: We now report the molecular lesion associated with the RFLP haplotype 2 mutant allele.

molecular lesion


Input: This defect is caused by a C-to-T transition in exon 12 resulting in an amino-acid substitution (Arg to Trp) at residue 408 of PAH.


Input: Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is also in linkage disequilibrium with RFLP haplotype 2 alleles that make up about 20% of mutant PAH genes


Input: Choroideremia: close linkage to DXYS1 and DXYS12 demonstrated by segregation analysis and historical-genealogical evidence.

Choroideremia


Input: Linkage studies using restriction fragment length polymorphisms were conducted in the X-linked disorder, choroideremia, designated TCD for Progressive Tapeto-Choroidal Dystrophy.

X-linked disorder

choroideremia

TCD

Progressive Tapeto-Choroidal Dystrophy


Input: Previously demonstrated close linkage with locus DXYS1 was confirmed (lod 11. 44 at 0 recombination distance).


Input: In addition, locus DXYS12 was found to be closely linked with TCD (lod 3. 31 at 0 recombination distance).

TCD


Input: The disease mainly occurs in three large kindreds in remote Northern Finland.


Input: While formal genealogical proof is lacking, all presently living (more than 80 affected males and 120 carrier females) probably originate from a common founder couple born in 1644 and 1646, twelve generations ago.


Input: All 36 patients and 48 carriers tested from the three kindreds had the same haplotype (TCD/DXYS1, 11kb/DXYS12, 1. 6kb).

TCD


Input: Given that at least 105 female meioses transmitting TCD have occurred since 1650 in these kindreds, extremely close linkage between TCD, DXYS1 and DXYS12 is suggested.

TCD

TCD


Input: The above haplotype is a very useful diagnostic tool in these TCD families.

TCD


Input: We suggest that our historical-genealogical approach to linkage analysis may be possible elsewhere in similar isolated populations


Input: Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma.

Von Hippel-Lindau disease

renal cell carcinoma


Input: Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas.

Von Hippel-Lindau disease

VHL

autosomal dominant disorder

cancer

hemangioblastomas

phaeochromocytomas

pancreatic malignancies

renal cell carcinomas


Input: Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type.

Renal cell carcinomas

bilateral and multifocal tumours

tumour


Input: We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4).

VHL


Input: Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself.

VHL

VHL


Input: An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative tumour suppressor which can be associated with both the inherited and sporadic forms of the cancer.

tumour

tumour

inherited and sporadic forms of the cancer


Input: Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6).

Sporadic renal cell carcinomas


Input: Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same tumour suppressor gene on this chromosome..

renal cell carcinoma

tumour


Input: Tightly linked flanking markers for the Lowe oculocerebrorenal syndrome, with application to carrier assessment.

Lowe oculocerebrorenal syndrome


Input: The Lowe oculocerebrorenal syndrome (OCRL) is characterized by congenital cataract, mental retardation, and defective renal tubular function.

Lowe oculocerebrorenal syndrome

OCRL

cataract

mental retardation

defective renal tubular function


Input: A map assignment of OCRL to Xq24-q26 has been made previously by linkage analysis with DXS42 at Xq24-q26 (theta = 0, z = 5. 09) and with DXS10 at Xq26 (theta = 0, z = 6. 45).

OCRL


Input: Two additional families were studied and three additional polymorphisms were identified at DXS42 by using a 35-kb sequence isolated with the probe detecting the original polymorphism at DXS42.


Input: With additional OCRL families made informative for DXS42, theta remained 0 with z = 6.

OCRL


Input: 63; and for DXS10 theta = 0.


Input: 03 and z = 7.


Input: Evidence for placing OCRL at Xq25 also comes from a female with Lowe syndrome and an X; 3 translocation.

Lowe syndrome


Input: We have used the Xq25 breakpoint in this patient to determine the position of OCRL relative to the two linked markers.


Input: Each derivative chromosome was isolated away from its normal counterpart in somatic cell hybrids.


Input: DXS42 was mapped to the derivative chromosome X containing Xpterq25, and DXS10 was mapped to the derivative chromosome 3 containing Xq25-qter.


Input: The markers DXS10 and DXS42 therefore show tight linkage with OCRL in six families and flank the Xq25 breakpoint in a female patient with an X; 3 translocation.

OCRL


Input: Linkage analysis with flanking markers was used to assess OCRL carrier status in women at risk.

OCRL


Input: Results, when compared with carrier determination by ophthalmologic examination, indicated that the slit-lamp exam can be a sensitive and specific method of carrier determination in many cases


Input: Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome


Input: Complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) causes the Lesch-Nyhan syndrome.

deficiency of hypoxanthine-guanine phosphoribosyltransferase

Lesch-Nyhan syndrome


Input: Previous characterization of a mutant form of HPRT, HPRTYale, from a subject with the Lesch-Nyhan syndrome revealed normal mRNA and protein concentrations, no residual catalytic activity, and cathodal migration upon PAGE.

Lesch-Nyhan syndrome


Input: We have cloned and sequenced HPRTYale cDNA.


Input: The nucleotide sequence of full-length HPRTYale cDNA revealed a single nucleotide substitution compared with normal HPRT cDNA G----C at nucleotide position 211.


Input: This transversion predicts substitution of arginine for glycine at amino acid position 71, explaining the cathodal migration of HPRTYale.


Input: Chou-Fasman secondary structure analysis predicts a change in the probability of beta-turn formation in the region containing the mutation.


Input: Inclusion of the bulky arginine side chain in place of glycine probably disrupts protein folding as well.


Input: Cloning mutant forms of cDNA allows identification of specific mutations, provides insight into mutational mechanisms, and facilitates structure-function analysis of mutant proteins..


Input: Two point mutations are responsible for G6PD polymorphism in Sardinia.


Input: The human X-linked gene encoding glucose 6-phosphate dehydrogenase (G6PD) is highly polymorphic; more than 300 G6PD variants have been identified.


Input: G6PD deficiency in different geographical areas appears to have arisen through independent mutational events, but within the same population it may also be heterogeneous.

G6PD deficiency


Input: One example is the island of Sardinia, where careful clinical and biochemical studies have identified four different G6PD variants.


Input: We cloned and sequenced the four G6PD variants from Sardinia and found that only two mutations are responsible for G6PD deficiency in this area one mutation is the cause of the G6PD Seattle-like phenotype, a milder form of G6PD deficiency; the other mutation is responsible for all forms of very severe G6PD deficiency in Sardinia and, possibly, in the Mediterranean..

G6PD deficiency

G6PD Seattle-like phenotype

G6PD deficiency

G6PD deficiency


Input: Chronic nonspherocytic hemolytic anemia (CNSHA) and glucose 6 phosphate dehydrogenase (G6PD) deficiency in a patient with familial amyloidotic polyneuropathy (FAP).

Chronic nonspherocytic hemolytic anemia

CNSHA

glucose 6 phosphate dehydrogenase (G6PD) deficiency

familial amyloidotic polyneuropathy

FAP


Input: Molecular study of a new variant (G6PD Clinic) with markedly acidic pH optimum.


Input: A new glucose-6-phosphate dehydrogenase (G6PD) variant with severe erythrocytic G6PD deficiency and a unique pH optimum is described in a young patient with chronic nonspherocytic hemolytic anemia (CNSHA) and familial amyloidotic polyneuropathy (FAP).

erythrocytic G6PD deficiency

chronic nonspherocytic hemolytic anemia

CNSHA

familial amyloidotic polyneuropathy

FAP


Input: Chronic hemolysis was present in the absence of infections, oxidant drugs or ingestion of faba beans.

Chronic hemolysis


Input: Residual enzyme activity was about 2.


Input: 6% and 63% of normal activity in erythrocytes and leucocytes, respectively.


Input: A molecular study using standard methods showed G6PD in the patient to have normal electrophoretic mobility (at pH 7. 0, 8. 0 and 8. 8), normal apparent affinity for substrates (Km, G6P and NADP) and a slightly abnormal utilization of substrate analogues (decreased deamino-NADP and increased 2-deoxyglucose-6-phosphate utilization).


Input: Heat stability was found to be markedly decreased (8% of residual activity after 20 min of incubation at 46 degrees C) and a particular characteristic of this enzyme was a biphasic pH curve with a greatly increased activity at low pH.


Input: Although molecular characteristics of this variant closely resemble those of G6PD Bangkok and G6PD Duarte, it can be distinguished from these and all other previously reported variants by virtue of its unusual pH curve.


Input: Therefore the present variant has been designated G6PD Clinic to distinguish it from other G6PD variants previously described


Input: Molecular detection of chromosomal translocations that disrupt the putative retinoblastoma susceptibility locus.

retinoblastoma


Input: A candidate DNA sequence with many of the properties predicted for the retinoblastoma susceptibility (RB1) locus has been cloned (S. H. Friend, R. Bernards, S. Rogelj, R. A. Weinberg, J. M. Rapaport, D. M. Albert, and T. P. Dryja, Nature [London] 323 643-645, 1986).

retinoblastoma


Input: The large size of this gene (ca. 200 kilobases [kb]) and its multiple dispersed exons (Wiggs et al., N. Engl. J. Med. 318 151-157, 1988) complicate molecular screening strategies important in prenatal and presymptomatic diagnosis and in carrier detection.


Input: Here we used field inversion gel electrophoresis (FIGE) to construct a restriction map of approximately 1, 000 kb of DNA surrounding the RB1 locus and to detect the translocation breakpoints in three retinoblastoma patients.

retinoblastoma


Input: DNA probes from either the 5 or 3 end of the gene were used to detect a 250-kb EagI restriction fragment in DNA from unaffected individuals.


Input: Both probes identified an additional hybridizing fragment in the DNA from each patient, permitting the breakpoints in all three to be mapped within the cloned RB1 gene.


Input: Analysis of the breakpoint in one translocation cell line allowed the RB1 gene to be oriented with its 5 end toward the centromere.


Input: The 5 end of the gene also appeared to be associated with a clustering of sites for several infrequently cleaving restriction enzymes, indicating the presence of an HpaII tiny fragment island.


Input: The detection and mapping of the translocation breakpoints of all three retinoblastoma patients to within the putative RB1 gene substantiated the authenticity of this candidate sequence and demonstrated the utility of FIGE in detecting chromosomal rearrangements affecting this locus.

retinoblastoma


Input: Inherited C3 deficiency with recurrent infections and glomerulonephritis.

C3 deficiency

glomerulonephritis


Input: A 10-year-old Laotian boy had homozygous deficiency of the third component of complement and recurrent bacterial infections beginning at age 5 months.

deficiency of the third component of complement

bacterial infections


Input: Cellular and humoral immunity were normal, as were polymorphonuclear leukocyte chemotaxis and bactericidal activities.


Input: Serum complement-mediated hemolytic, chemotactic, and opsonic activities were deficient.


Input: In vitro addition of purified C3 to patient serum restored hemolytic complement to normal levels, and plasma infusion during each of four episodes of pneumonia significantly enhanced serum opsonic activity for as long as 36 hours.

pneumonia


Input: A renal biopsy specimen revealed mesangiopathic glomerulonephritis, although significant levels of circulating IgG immune complexes were not detected.

mesangiopathic glomerulonephritis


Input: These findings further support the association of C3 deficiency with immune-complex disease and suggest that plasma infusion may be an adjunct to antibiotic therapy in the management of severe pyogenic infections in patients with C3 deficiency..

C3 deficiency

immune-complex disease

pyogenic infections

C3 deficiency


Input: DNA restriction fragments associated with alpha 1-antitrypsin indicate a single origin for deficiency allele PI Z.


Input: The alpha 1-protease inhibitor, or alpha-antitrypsin (AAT), a major plasma inhibitor of leukocyte elastase and bacterial proteases, is encoded at the PI locus on chromosome 14 (14q24. 3-q32. 1).


Input: A deficiency of AAT in individuals homozygous for the PI Z allele occurs in about 1 in 2, 000-8, 000 caucasians and is associated with an increased risk of early adult onset emphysema and liver disease in childhood.

deficiency of AAT

emphysema

liver disease


Input: We have now used DNA polymorphisms associated with the AAT gene to investigate the origin of the PI Z allele.


Input: Using two genomic probes extending into the 5 and 3 flanking regions, respectively, we have identified eight polymorphic restriction sites.


Input: Extensive linkage disequilibrium occurs throughout the probed region with the PI Z allele, but not with normal PI M alleles.


Input: The Z allele occurs mainly with one haplotype, indicating a single, relatively recent, origin in caucasians


Input: Segregation analysis of a marker localised Xp21. 2-Xp21. 3 in Duchenne and Becker muscular dystrophy families.

Duchenne and Becker muscular dystrophy


Input: A DNA marker C7, localised Xp21.


Input: 3, has been studied in kindreds segregating for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

Duchenne muscular dystrophy

DMD

Becker muscular dystrophy

BMD


Input: In DMD families four crossovers were observed in 38 informative meioses between C7 and the DMD locus (theta = 0. 12, z max = + 2. 72).

DMD

DMD


Input: In BMD families no recombinants were observed in the 16 informative meioses studied.

BMD


Input: These data are consistent with the localisation of the mutations in these disorders being in the same region of Xp21.


Input: Studies in families also segregating for the DNA marker 754 support the previously reported physical order of these loci as X centromere-754-DMD-BMD-C7-X telomere.


Input: A recombination fraction of 0.


Input: 11 (z max = + 5. 58) was found between DMD-754 by combining our previously published data with the data presented here.


Input: C7 and 754 thus provide good bridging markers for the diagnosis of DMD and BMD

DMD


Input: Isolation of molecular probes associated with the chromosome 15 instability in the Prader-Willi syndrome.

Prader-Willi syndrome


Input: Flow cytometry and recombinant DNA techniques have been used to obtain reagents for a molecular analysis of the Prader-Willi syndrome (PWS).

Prader-Willi syndrome

PWS


Input: HindIII total-digest libraries were prepared in lambda phage Charon 21A from flow-sorted inverted duplicated no. 15 human chromosomes and propagated on recombination-proficient (LE392) and recBC-, sbcB-(DB1257) bacteria.


Input: Twelve distinct chromosome 15-specific probes have been isolated.


Input: Eight localized to the region 15q11----13.


Input: Four of these eight sublocalized to band 15q11.


Input: 2 and are shown to be deleted in DNA of one of two patients examined with the PWS.

PWS


Input: Heteroduplex analysis of two of these clones, which grew on DB1257 but not on LE392, revealed stem-loop structures in the inserts, indicative of inverted, repeated DNA elements.


Input: Such DNA repeats might account for some of the cloning instability of DNA segments from proximal 15q.


Input: Analysis of the genetic and physical instability associated with the repeated sequences we have isolated from band 15q11.


Input: 2 may elucidate the molecular basis for the instability of this chromosomal region in patients with the PWS or other diseases associated with chromosomal abnormalities in the proximal long arm of human chromosome 15

PWS

chromosomal abnormalities


Input: Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy.

Becker and Duchenne muscular dystrophy


Input: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder for which the biochemical defect is as yet unknown.

Duchenne muscular dystrophy

DMD

X-linked recessive genetic disorder


Input: Recently, two cloned segments of human X-chromosome DNA have been described which detect structural alterations within or near the genetic locus responsible for the disorder.


Input: Both of these cloned segments were described as tightly linked to the locus and were capable of detecting deletions in the DNA of boys affected with DMD.

DMD


Input: In an attempt to determine more precisely the occurrence of these deletions within a large population of DMD patients and the accuracy of one of the segments, DXS164 (pERT87), in determining the inheritance of the DMD X chromosome, the subclones 1, 8 and 15 were made available to many investigators throughout the world.

DMD

DMD


Input: Here we describe the combined results of more than 20 research laboratories with respect to the occurrence of deletions at the DXS164 locus in DNA samples isolated from patients with DMD and Becker muscular dystrophy (BMD).

DMD

Becker muscular dystrophy

BMD


Input: The results indicate that the DXS164 locus apparently recombines with DMD 5% of the time, but is probably located between independent sites of mutation which yield DMD.

DMD

DMD


Input: The breakpoints of some deletions are delineated within the DXS164 locus, and it is evident that the deletions at the DMD locus are frequent and extremely large..

DMD


Input: A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice.

Lesch-Nyhan syndrome


Input: The human Lesch-Nyhan syndrome is a rare neurological and behavioural disorder, affecting only males, which is caused by an inherited deficiency in the level of activity of the purine salvage enzyme hypoxanthine-guanosine phosphoribosyl transferase (HPRT).

Lesch-Nyhan syndrome

neurological and behavioural disorder

inherited deficiency


Input: How the resulting alterations in purine metabolism lead to the severe symptoms characteristic of Lesch-Nyhan patients is still not understood.

Lesch-Nyhan


Input: No mutations at the Hprt locus leading to loss of activity have been described in laboratory animals.


Input: To derive an animal model for the Lesch-Nyhan syndrome, we have used cultured mouse embryonic stem cells, mutagenized by retroviral insertion and selected for loss of HPRT activity, to construct chimaeric mice.

Lesch-Nyhan syndrome


Input: Two clonal lines carrying different mutant Hprt alleles have given rise to germ cells in chimaeras, allowing the derivation of strains of mutant mice having the same biochemical defect as Lesch-Nyhan patients.

Lesch-Nyhan


Input: Male mice carrying the mutant alleles are viable and analysis of their cells shows a total lack of HPRT activity..


Input: Re-evaluation of the sublocalization of esterase D and its relation to the retinoblastoma locus by in situ hybridization.

retinoblastoma


Input: In situ hybridization of a cDNA probe for the esterase D gene (ESD) was carried out on human chromosomes.


Input: The probe hybridized most strongly to 13q14.


Input: 2 and 13q14.


Input: This observation raises doubts concerning the most recently published assignment of ESD to 13q14.


Input: A deletion in an individual with retinoblastoma was reported to separate the closely linked ESD and retinoblastoma (RB1) loci, placing ESD proximal to RB1.

retinoblastoma

retinoblastoma


Input: Quantitative in situ hybridization studies of this deletion do not confirm this interpretation.


Input: Rather, they suggest that ESD is missing from the deleted chromosome 13 and duplicated on the normal homolog.


Input: From these findings, we conclude that the deletion in this individual cannot be used to determine the orientation nor the sublocalization of ESD and RB1 within the 13q14 region.


Input: Hereditary C2 deficiency associated with common variable immunodeficiency.

Hereditary C2 deficiency

immunodeficiency


Input: Homozygous C2 deficiency in a 19-year-old boy was associated with variable immunodeficiency manifested by marked hypoimmunoglobulinemia and impaired antibody responses, normal circulating B lymphocytes, and subnormal T-cell functions.

C2 deficiency

immunodeficiency

hypoimmunoglobulinemia


Input: Neither antilymphocytic autoantibodies nor chromosomal abnormalities were found.

chromosomal abnormalities


Input: Serum immunoglobulin levels were within normal limits in his parents and brother who were heterozygous for C2 deficiency.

C2 deficiency


Input: The patients lymphocytes were homozygous at the HLA-D locus but expressed an antigen different from DW2..


Input: Mild and severe muscular dystrophy associated with deletions in Xp21 of the human X chromosome.

muscular dystrophy


Input: We have analysed over 300 patients suffering from Duchenne or Becker muscular dystrophy (DMD or BMD).

Duchenne or Becker muscular dystrophy

DMD

BMD


Input: Deletions have been characterised which encompass either the pERT87 (DXS164) locus only, the XJ1.


Input: 1 (DXS206) and HIP25 loci only, or all three loci.


Input: These loci have been shown to lie within the DMD region covering several hundred kilobases (kb) of DNA.

DMD


Input: One mildly affected BMD patient possesses a deletion of at least 110 kb including exons of the DMD gene.

BMD

DMD


Input: Other patients with similar exon deletions, or smaller deletions, show the more severe phenotype typical of DMD.

DMD


Input: We conclude from these studies that the severity of the clinical phenotype cannot be explained on the basis of the size of the deletion.


Input: We discuss this in the context of candidate gene sequences.


Input: Patterns of exon deletions in Duchenne and Becker muscular dystrophy.

Duchenne and Becker muscular dystrophy


Input: A panel of patients with Duchenne and Becker muscular dystrophy (DMD and BMD) has been screened with the cDNA probes Cf56a and Cf23a, which detect exons in the central part of the DMD gene.

Duchenne and Becker muscular dystrophy

DMD

BMD

DMD


Input: One or more exons were deleted in 60% of patients.


Input: The deletions were mapped and prove to be heterogeneous in size and extent, particularly in DMD.

DMD


Input: Deletions specific to DMD and to BMD are described.

DMD

BMD


Input: Half of all BMD patients have a deletion of one particular small group of exons; smaller deletions within this same group produce the more severe DMD..

BMD

DMD


Input: Hereditary deficiency of the third component of complement in a child with fever, skin rash, and arthralgias: response to transfusion of whole blood.

Hereditary deficiency of the third component of complement

fever

skin rash

arthralgias


Input: A previously well 34-month-old male presenting with fever, skin rash, and arthralgias was found to lack C3 by immunochemical (undetectable) and hemolytic (1% normal) assays.

fever

skin rash

arthralgias


Input: No infectious agent could be demonstrated.


Input: Protein levels of Clq.


Input: C4, C5, properdin, and C3b-INA and hemolytic activities of complement components C1 to C9 except C3 were normal or elevated; total hemolytic complement activity was 13% of normal and was reconstituted by purified C3.


Input: Properdin factor B was 702 (normal 175 to 275) mug/ml, and was not cleaver upon addition of zymosan or cobra venom factor.


Input: The serum had normal immune adherence activity, but was deficient in ability to opsonize Candida albicans for uptake and Escherichia coli for killing by neurophils, generate neutrophil chemotactic factors and inhibit the growth of E. coli; these activities were restored by purified C3.


Input: A transfusion of 320 ml 1-hour-old normal whole blood on the fifty-second day resulted in transitory elevation of the C3 level to 25 mg/dl with a fall-off (approximately 2 1/2% per hour) to undetectable levels by 69 hours; it was followed by disappearance of the skin rash and arthralgias and return to normal of the previously elevated temperature and CRP levels.

skin rash

arthralgias


Input: C3 levels in family members (seven of 24 half-normal), lack of anti-C3 activity, normal C3b-INA levels and a normal rate of catabolism of transfused C3 indicated that the deficiency was inherited with autosomal codominance and involved decreased synthesis of C3.

decreased synthesis of C3


Input: Thus, this child is a unique individual with inherited C3 deficiency presenting with absence of repeated infections, whose symptoms of fever, skin rash, and arthralgia were abated by whole blood transfusion..

inherited C3 deficiency

fever

skin rash

arthralgia


Input: Glucose-6-phosphate dehydrogenase variants and their frequency in Guangdong, China.


Input: Erythrocyte glucose-6-phosphate dehydrogenase (G6PD) was characterized in blood samples obtained from 97 randomly selected males with enzyme deficiency from various regions of Guangdong Province, China.

enzyme deficiency


Input: Nine new variants (Gd Kaiping, Gd Boluo, Gd Huiyang, Gd Gaomin, Gd Qing-Baijiang, Gd Gaozhou, Gd Huazhou, Gd Nanhai, and Gd Guangzhou) were identified.


Input: Of the 31 variants found in this province, Gd Kaiping, Gd Taiwan-Hakka, Gd Haad Yai, Gd Haad Yai-like and Gd Huiyang occurred most frequently.


Input: The frequency of each variant was calculated.


Input: The results demonstrated that the genetic heterogeneity of G6PD deficiency was high in this area..

G6PD deficiency


Input: Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease.

von Willebrand

severe von Willebrand disease


Input: Severe von Willebrand disease is characterized by undetectable or trace quantities of von Willebrand factor in plasma and tissue stores.

Severe von Willebrand disease

von Willebrand


Input: We have studied the genomic DNA of 10 affected individuals from six families with this disorder using probes from the 5 and 3 ends of the vWF cDNA and with a probe extending from the 5 end into the central region.


Input: Southern blots of restriction endonuclease digests and gene dosage analysis measurements carried out with quantitative slot blots of undigested genomic DNA separated these patients into three groups.


Input: The first group consisted of a family with complete homozygous deletions of the vWF gene in the four probands.


Input: Gene dosage analysis was consistent with heterozygous deletions in both of the asymptomatic parents and four asymptomatic siblings of this kindred (P less than 0. 01).


Input: The second group was comprised of a family in which there was a complete heterozygous deletion of the vWF gene in the proband and one asymptomatic parent, suggesting that a different type of genetic abnormality was inherited from the other parent.

genetic abnormality


Input: Thus, the patient appeared to be doubly heterozygous for interacting genetic abnormalities affecting vWF expression.

genetic abnormalities


Input: In the third group, no gene deletions could be detected.


Input: Alloantibodies developed only in the kindred with homozygous deletions.


Input: These techniques should prove useful in identifying carriers of severe von Willebrand disease and also in defining patients predictably at risk of developing alloantibodies to vWF.

severe von Willebrand disease


Input: Sjogren-Larsson syndrome.

Sjogren-Larsson syndrome


Input: Impaired fatty alcohol oxidation in cultured fibroblasts due to deficient fatty alcohol: nicotinamide adenine dinucleotide oxidoreductase activity.


Input: Lipid metabolism was studied in cultured skin fibroblasts from patients with the inherited disorder, Sjogren-Larsson syndrome (SLS).

inherited disorder

Sjogren-Larsson syndrome

SLS


Input: Intact SLS fibroblasts incubated in the presence of [1-14C] palmitate accumulated more radioactive hexadecanol than did normal cells, whereas incorporation of radioactivity into other cellular lipids was unaltered.

SLS


Input: The hexadecanol content of SLS fibroblasts was abnormally elevated.

SLS


Input: Hexadecanol accumulation was not due to increased fatty alcohol synthesis nor its deficient utilization for glycerol ether synthesis.


Input: The half-life of intracellular hexadecanol loaded into SLS fibroblasts was increased (70 min) compared with normal (15 min), and intact SLS fibroblasts showed impaired oxidation of [14C]-hexadecanol to fatty acid.

SLS

SLS


Input: Fatty alcohol NAD + oxidoreductase, the enzyme catalyzing this reaction, was deficient in SLS fibroblasts.

SLS


Input: Mean total activity in SLS fibroblasts (n = 5) was 13% of that in normal fibroblasts, and palmitoyl CoA-inhibitable activity was 1% of normal.

SLS


Input: Fibroblasts from two obligate SLS heterozygotes had enzyme activities intermediate between that in normal fibroblasts and individuals with SLS.

SLS

SLS


Input: These results suggest that the primary defect in SLS is deficiency of fatty alcohol NAD + oxidoreductase.

SLS

deficiency of fatty alcohol NAD + oxidoreductase


Input: SLS represents the first inherited disorder in man associated with an isolated abnormality in fatty alcohol metabolism..

SLS

inherited disorder

abnormality in fatty alcohol metabolism


Input: Germinal mosaicism in Duchenne muscular dystrophy.

Duchenne muscular dystrophy


Input: We have identified a Duchenne muscular dystrophy (DMD) pedigree where the disease is associated with a molecular deletion within the DMD locus.

Duchenne muscular dystrophy

DMD

DMD


Input: We have examined the meiotic segregation products of the common female ancestor using marker restriction fragment length polymorphisms (RFLPs) detected by probes that lie within this deletion.


Input: These studies show that this female has transmitted three distinct types of X chromosome to her offspring.


Input: This observation may be explained by postulating that the mutation arose as a postzygotic deletion within this common ancestor, who was consequently germinally mosaic..


Input: Nebulin seen in DMD males including one patient with a large DNA deletion encompassing the DMD gene.

DMD

DMD


Input: The presence of nebulin in a muscle specimen from a patient with Duchenne muscular dystrophy (DMD) due to a large deletion precludes the possibility that this protein is the DMD gene product..

Duchenne muscular dystrophy

DMD

DMD


Input: Expression of the murine Duchenne muscular dystrophy gene in muscle and brain.

Duchenne muscular dystrophy


Input: Complementary DNA clones were isolated that represent the 5 terminal 2.


Input: 5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA).

Duchenne muscular dystrophy


Input: Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain.


Input: Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice.

dystrophic


Input: The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males.

Duchenne muscular dystrophy

DMD

mental retardation

DMD


Input: These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations.


Input: Glucose 6-phosphate dehydrogenase deficiency and incidence of hematologic malignancy.

Glucose 6-phosphate dehydrogenase deficiency

hematologic malignancy


Input: We have evaluated the hypothesis of a negative association between glucose 6-phosphate dehydrogenase (G6PD) deficiency and cancer in a cohort of 481 Sardinian males with hematological malignancies.

glucose 6-phosphate dehydrogenase (G6PD) deficiency

cancer

hematological malignancies


Input: The frequency of G6PD deficiency in the patients was not different from the incidence in a group of 16, 219 controls.

G6PD deficiency


Input: The same conclusion resulted from the comparison of the frequency of expression of the GdB gene in 23 heterozygous women having a clonal hematologic disease and a control group of 37 healthy heterozygotes.

hematologic disease


Input: Therefore at present there is no evidence that G6PD deficiency has a protective effect against development of hematologic neoplasms..

G6PD deficiency

hematologic neoplasms


Input: Hepatoblastoma, pigmented ocular fundus lesions and jaw lesions in Gardner syndrome.

Hepatoblastoma

pigmented ocular fundus lesions

jaw lesions

Gardner syndrome


Input: Hepatoblastoma is a rare neoplasm of infants and children only recently documented in association with hereditary adenomatous polyposis of the colon [Kingston et al., 1983].

Hepatoblastoma

neoplasm

hereditary adenomatous polyposis of the colon


Input: We report four children with hepatoblastoma from four unrelated families with Gardner syndrome (GS).

hepatoblastoma

Gardner syndrome

GS


Input: One child, now 19 years old, survived after a resection of a hepatoblastoma in infancy and recently was found to have GS.

hepatoblastoma

GS


Input: He has an associated odontoma and pigmented ocular fundus lesions, both of which have been shown to be clinical markers of GS.

odontoma

pigmented ocular fundus lesions

GS


Input: Many individuals in these four GS families, both affected and at risk, have osteomatous jaw lesions and pigmented ocular fundus lesions.

GS

osteomatous jaw lesions

pigmented ocular fundus lesions


Input: A search for colonic polyps should be made in families of infants and children with hepatoblastoma.

colonic polyps

hepatoblastoma


Input: If the child survives, he or she should be monitored for the later appearance of colonic polyps.

colonic polyps


Input: The finding of jaw lesions and/or pigmented ocular fundus lesions in relatives at risk are indications of the possible presence of the GS gene.

jaw lesions

pigmented ocular fundus lesions

GS


Input: Identification of an altered splice site in Ashkenazi Tay-Sachs disease.

Tay-Sachs disease


Input: Tay-Sachs disease is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (ref. 1).

Tay-Sachs disease

autosomal recessive genetic disorder


Input: A relatively high frequency of carriers (1/27) of a lethal, infantile form of the disease is found in the Ashkenazi Jewish population, but it is not yet evident whether this has resulted from a founder effect and random genetic drift or from a selective advantage of heterozygotes.


Input: We have identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient.


Input: This change, the substitution of a C for G in the first nucleotide of intron 12 is expected to result in defective splicing of the messenger RNA.


Input: A test for the mutant allele based on amplification of DNA by the polymerase chain rection and cleavage of a DdeI restriction site generated by the mutation revealed that this case and two other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for two different mutations.

Tay-Sachs disease


Input: The occurrence of multiple mutant alleles warrants further examination of the selective advantage hypothesis..


Input: X-linked glucose-6-phosphate dehydrogenase deficiency in Mus musculus.

X-linked glucose-6-phosphate dehydrogenase deficiency


Input: A mouse with X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency has been recovered in offspring of 1-ethyl-1-nitrosourea-treated male mice.

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency


Input: The activity alteration was detected in blood but can also be observed in other tissue extracts.


Input: Hemizygous, heterozygous, and homozygous mutants have, respectively, about 15, 60, and 15% G6PD remaining activity in the blood as compared to the wild type.


Input: Erythrocyte indices did not show differences between mutants and wild types.


Input: The mutation does not affect the electrophoretic migration, the isoelectric point, or the thermal stability.


Input: Kinetic properties, such as the Km for glucose-6-phosphate or for NADP and the relative utilization of substrate analogues, showed no differences between wild types and mutants with the exception of the relative utilization of deamino-NADP which was significantly lower in mutants.


Input: This is presently the only animal model for X-linked G6PD deficiency in humans..

X-linked G6PD deficiency


Input: Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia.

enzyme deficiency

hemolytic anemia


Input: Glucose-6-phosphate dehydrogenase (G6PD; EC 1. 1. 1. 49) deficiency is a common genetic abnormality affecting an estimated 400 million people worldwide.

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

genetic abnormality


Input: Clinical and biochemical analyses have identified many variants exhibiting a range of phenotypes, which have been well characterized from the hematological point of view.


Input: However, until now, their precise molecular basis has remained unknown.


Input: We have cloned and sequenced seven mutant G6PD alleles.


Input: In the nondeficient polymorphic African variant G6PD A we have found a single point mutation.


Input: The other six mutants investigated were all associated with enzyme deficiency.

enzyme deficiency


Input: In one of the commonest, G6PD Mediterranean, which is associated with favism among other clinical manifestations, a single amino acid replacement was found (serine----phenylalanine) it must be responsible for the decreased stability and the reduced catalytic efficiency of this enzyme.

favism


Input: Single point mutations were also found in G6PD Metaponto (Southern Italy) and in G6PD Ilesha (Nigeria), which are asymptomatic, and in G6PD Chatham, which was observed in an Indian boy with neonatal jaundice.

neonatal jaundice


Input: In G6PD " Matera, " which is now known to be the same as G6PD A-, two separate point mutations were found, one of which is the same as in G6PD A.


Input: In G6PD Santiago, a de novo mutation (glycine----arginine) is associated with severe chronic hemolytic anemia.

hemolytic anemia


Input: The mutations observed show a striking predominance of C----T transitions, with CG doublets involved in four of seven cases.


Input: Thus, diverse point mutations may account largely for the phenotypic heterogeneity of G6PD deficiency.

G6PD deficiency


Input: Tight linkage between myotonic dystrophy and apolipoprotein E genes revealed with allele-specific oligonucleotides.

myotonic dystrophy


Input: In 16 families with myotonic dystrophy (DM) a novel approach based on use of allele-specific oligonucleotides has been employed to study the linkage relationship between the apolipoprotein E (APOE) gene and DM.

myotonic dystrophy

DM

DM


Input: Synthetic oligonucleotides, designed to discriminate between APOE alleles epsilon 3 and epsilon 4, enabled us to distinguish heterozygous carriers in a hybridization assay.


Input: In a subset of families, the relevant segment of the APOE gene was enzymatically amplified to increase the sensitivity of the method.


Input: For DM and APOE, a maximum lod score (zmax of 7.


Input: 47 was obtained at a recombination frequency (theta) of 0.


Input: 047 (male theta = female theta).


Input: No recombination (maximum lod score of 5. 61 at theta = 0. 0) was found between APOE and the apolipoprotein CII (APOC2) gene.


Input: These results suggest that, in addition to APOC2, APOE is a useful marker for presymptomatic DM diagnosis.

DM


Input: Regional localization of polymorphic DNA loci on the proximal long arm of the X chromosome using deletions associated with choroideremia.

choroideremia


Input: In two unrelated families, males have been identified who suffer from choroideremia and at the same time have an interstitial deletion on the proximal long arm of the X chromosome.

choroideremia


Input: By high-resolution banding we have characterized the deletion chromosomes as del (X) (q21. 1-q21 1-q21. 33) and del (X) (q21. 2-q21 2-q21. 31) respectively.


Input: By Southern blot analysis we have mapped ten different polymorphic DNA loci relative to the position of the deletion and the choroideremia locus TCD.

choroideremia


Input: One probe, p31, was shown to cover one of the breakpoints of the smallest deletion.


Input: The following order of the loci was suggested by deletion mapping cen-DXS106-DXS72-TCD-(DXYS1/DXYS23/DXYS5)-DXYS2-(DXYS12/DXS3)-(DXS17/DXS101)-Xqter.


Input: Retroviral-mediated gene transfer of human phenylalanine hydroxylase into NIH 3T3 and hepatoma cells.

hepatoma


Input: Phenylketonuria (PKU) is caused by deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH).

Phenylketonuria

PKU

deficiency of the hepatic enzyme phenylalanine hydroxylase


Input: A full-length human PAH cDNA sequence has been inserted into pzip-neoSV (X), which is a retroviral vector containing the bacterial neo gene.


Input: The recombinant has been transfected into psi 2 cells, which provide synthesis of the retroviral capsid.


Input: Recombinant virus was detected in the culture medium of the transfected psi 2 cells, which is capable of transmitting the human PAH gene into mouse NIH 3T3 cells by infection leading to stable incorporation of the recombinant provirus.


Input: Infected cells express PAH mRNA, immunoreactive PAH protein, and exhibit pterin-dependent phenylalanine hydroxylase activity.


Input: The recombinant virus is also capable of infecting a mouse hepatoma cell line that does not normally synthesize PAH.

hepatoma


Input: PAH activity is present in the cellular extracts and the entire hydroxylation system is reconstituted in the hepatoma cells infected with the recombinant viruses.

hepatoma


Input: Thus, recombinant viruses containing human PAH cDNA provide a means for introducing functional PAH into mammalian cells of hepatic origin and can potentially be introduced into whole animals as a model for somatic gene therapy for PKU..

PKU


Input: Estimation of the male to female ratio of mutation rates from the segregation of X-chromosomal DNA haplotypes in Duchenne muscular dystrophy families.

Duchenne muscular dystrophy


Input: A novel procedure is presented to estimate the ratio of male to female mutation rates for Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy

DMD


Input: X-specific restriction fragment length polymorphisms are used to establish DNA haplotypes in three-generation DMD families.

DMD


Input: From the proportion of DMD patients who have inherited their maternal grandfathers X chromosome, the ratio of mutation rates can be calculated.

DMD


Input: In contrast to classical methods, the proposed procedure is not restricted to sporadic or familiar cases nor is any information on the carrier status of female relatives required..


Input: Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein.

retinoblastomas

mesenchymal tumors