Input: Retinoblastoma is a childhood tumor that can arise because of mutant alleles acquired as somatic or germinal mutations.

Retinoblastoma

childhood tumor


Input: The mutant allele can be carried in the germ line.


Input: The mutations creating these alleles act by inactivating copies of a recessive oncogene located within band q14 of chromosome 13 and termed the RB1 locus.


Input: We have reported isolation of a cDNA fragment that recognizes chromosomal sequences possessing many of the attributes of the retinoblastoma gene associated with the RB1 locus.

retinoblastoma


Input: We now report that this segment is additionally the target of somatic mutations in mesenchymal tumors among patients having no apparent predisposition to retinoblastoma and no previous evidence of retinoblastoma.

mesenchymal tumors

retinoblastoma

retinoblastoma


Input: These tumors provide additional evidence that the cloned sequences are representative of a gene that is a frequent target of inactivation during tumorigenesis.

tumors


Input: Sequence analysis of this cDNA provides little insight into its normal functional role..


Input: Treatment of Duchenne muscular dystrophy with growth hormone inhibitors.

Duchenne muscular dystrophy


Input: A controlled, double-blind therapeutic trial with the drug mazindol, a growth hormone inhibitor, was performed in a pair of 7 1/2 year-old monozygotic twins, with Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy

DMD


Input: The rationale for this trial was based on a patient (reported previously) affected simultaneously with DMD and growth hormone (GH) deficiency, who is showing a benign course of the dystrophic process and is still walking at 18 years.

DMD

growth hormone (GH) deficiency

dystrophic process


Input: One of the twins received 2 mg of mazindol daily, while the other received a placebo.


Input: The assessment, repeated every 2 months, included weight and height measurements, functional and motor ability tests, ergometry and determinations of serum enzymes and GH levels.


Input: After one year of trial the code was broken and it was seen that the twin under placebo treatment was strikingly worse than his brother, the progression of whose condition was practically arrested.


Input: These results strongly suggest that treatment with a GH inhibitor is beneficial for DMD patients..

DMD


Input: Identification and localization of mutations at the Lesch-Nyhan locus by ribonuclease A cleavage.

Lesch-Nyhan


Input: Many mutations leading to human disease are the result of single DNA base pair changes that cannot be identified by Southern analysis.


Input: This has prompted the development of alternative assays for point mutation detection.


Input: The recently described ribonuclease A cleavage procedure, with a polyuridylic acid-paper affinity chromatography step, has been used to identify the mutational lesions in the hypoxanthine phosphoribosyltransferase (HPRT) messenger RNAs of patients with Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome


Input: Distinctive ribonuclease A cleavage patterns were identified in messenger RNA from 5 of 14 Lesch-Nyhan patients who were chosen because no HPRT Southern or Northern blotting pattern changes had been found.

Lesch-Nyhan


Input: This approach now allows HPRT mutation detection in 50 percent of the cases of Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome


Input: The polyuridylic acid-paper affinity procedure provides a general method for analysis of low abundance messenger RNAs..


Input: Two new variants of glucose-6-phosphate dehydrogenase associated with hereditary non-spherocytic hemolytic anemia: G6PD Wayne and G6PD Huron.

hereditary non-spherocytic hemolytic anemia


Input: Two new deficient variants of glucose-6-phosphate dehydrogenase (G6PD) causing hereditary nonspherocytic hemolytic anemia (HNSHA) are described.

hereditary nonspherocytic hemolytic anemia

HNSHA


Input: Both of these are unique and they have been named G6PD Wayne and G6PD Huron.


Input: Patients with G6PD Wayne underwent splenectomy and no objective improvement was noted.


Input: The patients with G6PD Huron were under medical observation for a considerable period of time without the diagnosis of G6PD deficiency being entertained because the family was of Northern European origin.

G6PD deficiency


Input: Since sporadic variants of G6PD causing HNSHA show no special racial predilection, the diagnosis of G6PD deficiency should always be considered in patients with this syndrome..

HNSHA

G6PD deficiency


Input: Sialophorin, a surface sialoglycoprotein defective in the Wiskott-Aldrich syndrome, is involved in human T lymphocyte proliferation.

Wiskott-Aldrich syndrome


Input: The mAb L10 was used to determine the distribution and the function of sialophorin, the heavily glycosylated surface molecule that is deficient/defective in lymphocytes of patients with the X-linked immunodeficiency Wiskott-Aldrich syndrome.

X-linked immunodeficiency Wiskott-Aldrich syndrome


Input: Dual-parameter FACS analysis indicated that sialophorin is expressed on CD4 + and CD8 + lymphocytes, on a subpopulation of peripheral blood B lymphocytes, on all thymocytes, and on a subpopulation of bone marrow cells.


Input: Functional studies demonstrated that L10 mAb stimulates the proliferation of peripheral blood T lymphocytes as measured by stimulation of [3H] thymidine incorporation.


Input: The time course and magnitude of increased [3H] thymidine incorporation by T lymphocytes in response to L10 mAb paralleled that induced by anti-CD3 mAb.


Input: Effective stimulation was dependent on the presence of monocytes and the Fc portion of L10 mAb.


Input: Stimulation of lymphocytes by L10, like stimulation by anti-CD3 mAb, involves increased expression of 4F2, HLA-DR, and IL-2-R.


Input: These observations suggest that sialophorin functions in T cell activation..


Input: Hypopigmentation in the Prader-Willi syndrome.

Hypopigmentation

Prader-Willi syndrome


Input: Cutaneous and ocular pigmentation were evaluated in 29 individuals with the Prader-Willi syndrome (PWS).

Cutaneous and ocular pigmentation

Prader-Willi syndrome

PWS


Input: Criteria for hypopigmentation included the presence of type I or II skin, the lightest skin type in the family by history, and iris translucency on globe transillumination.

hypopigmentation


Input: On the basis of these criteria, 48% of the PWS individuals were hypopigmented.

PWS

hypopigmented


Input: The presence of hypopigmentation correlated with a small interstitial deletion on the proximal long arm of chromosome 15; however, this deletion was also found in individuals who did not meet the full criteria for hypopigmentation.

hypopigmentation

hypopigmentation


Input: Hairbulb tyrosinase activity and glutathione content, as well as urine cysteinyldopa excretion, were low in PWS individuals with and without hypopigmentation and did not separate these two groups.

PWS

hypopigmentation


Input: We conclude that hypopigmentation is found in a significant proportion of individuals with PWS and that the hypopigmentation may be associated with a deletion of the long arm of chromosome 15.

hypopigmentation

PWS

hypopigmentation


Input: The mechanism for the hypopigmentation is unknown..

hypopigmentation


Input: Phenotype heterogeneity among hemizygotes in a family biochemically screened for adrenoleukodystrophy.

adrenoleukodystrophy


Input: We report on two clinically, neurologically normal relatives of a boy affected by adrenoleukodystrophy (ALD); they were found repeatedly to have the biochemical defect of an ALD hemizygote.

adrenoleukodystrophy

ALD

ALD


Input: The assay consisted in the determination of very-long-chain fatty acids in lyophilized and reconstituted plasma.


Input: While no evidence of neurologic disease (leukodystrophy or myeloneuropathy) was present in these hemizygotes, adrenocortical insufficiency provoking compensatory high ACTH release was found in both.

neurologic disease

leukodystrophy

myeloneuropathy

adrenocortical insufficiency


Input: These findings should be taken into consideration when counseling families in which cases with clinically expressed ALD are represented in several generations..

ALD


Input: The mapping of a cDNA from the human X-linked Duchenne muscular dystrophy gene to the mouse X chromosome.

X-linked Duchenne muscular dystrophy


Input: The recent discovery of sequences at the site of the Duchenne muscular dystrophy (DMD) gene in humans has opened up the possibility of a detailed molecular analysis of the genes in humans and in related mammalian species.

Duchenne muscular dystrophy

DMD


Input: Until relatively recently, there was no obvious mouse model of this genetic disease for the development of therapeutic strategies.

genetic disease


Input: The identification of a mouse X-linked mutant showing muscular dystrophy, mdx, has provided a candidate mouse genetic homologue to the DMD locus; the relatively mild pathological features of mdx suggest it may have more in common with mutations of the Becker muscular dystrophy type at the same human locus, however.

muscular dystrophy

DMD

Becker muscular dystrophy


Input: But the close genetic linkage of mdx to G6PD and Hprt on the mouse X chromosome, coupled with its comparatively mild pathology, have suggested that the mdx mutation may instead correspond to Emery Dreifuss muscular dystrophy which itself is closely linked to DNA markers at Xq28-qter in the region of G6PD on the human X chromosome.

Emery Dreifuss muscular dystrophy


Input: Using an interspecific mouse domesticus/spretus cross, segregating for a variety of markers on the mouse X chromosome, we have positioned on the mouse X chromosome sequences homologous to a DMD cDNA clone.

DMD


Input: These sequences map provocatively close to the mdx mutation and unexpectedly distant from sparse fur, spf, the mouse homologue of OTC (ornithine transcarbamylase) which is closely linked to DMD on the human X chromosome..

DMD


Input: Localization of the region homologous to the Duchenne muscular dystrophy locus on the mouse X chromosome.

Duchenne muscular dystrophy


Input: Recent progress has resulted in part of the gene mutated in Duchenne and the milder Becker muscular dystrophies being cloned and has suggested that the gene itself extends over 1, 000 to 2, 000 kilobases (kb).

Duchenne and the milder Becker muscular dystrophies


Input: To study how mutations in this gene affect muscle development and integrity, it would be of interest to have available a mouse model of the human disease.


Input: The mouse mdx mutation affects muscle and confers a mild dystrophic syndrome, but it is not clear whether this mutation is equivalent to Duchenne/Becker muscular dystrophy in man.

dystrophic syndrome

Duchenne/Becker muscular dystrophy


Input: Here we describe the use of two sequences from the human Duchenne muscular dystrophy (DMD) gene that cross-hybridize to mouse X-linked sequences to localize the gene homologous to DMD in the mouse.

Duchenne muscular dystrophy

DMD

DMD


Input: Both sequences map to the region of 10 centimorgan lying between the Tabby (Ta) and St14-1 (DxPas8) loci, close to the phosphorylase b kinase locus (Phk).


Input: By analogy with the human X-chromosome, we conclude that the region in the mouse around the G6pd and St14-1 loci may contain two genes corresponding to distinct human myopathies Emery Dreifuss muscular dystrophy which is known to be closely linked to St14-1 in man and the DMD homologue described here..

myopathies Emery Dreifuss muscular dystrophy

DMD


Input: GT to AT transition at a splice donor site causes skipping of the preceding exon in phenylketonuria.

phenylketonuria


Input: Classical Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH).

Classical Phenylketonuria

PKU

autosomal recessive human genetic disorder

deficiency of hepatic phenylalanine hydroxylase


Input: We isolated several mutant PAH cDNA clones from a PKU carrier individual and showed that they contained an internal 116 base pair deletion, corresponding precisely to exon 12 of the human chromosomal PAH gene.

PKU


Input: The deletion causes the synthesis of a truncated protein lacking the C-terminal 52 amino acids.


Input: Gene transfer and expression studies using the mutant PAH cDNA indicated that the deletion abolishes PAH activity in the cell as a result of protein instability.


Input: To determine the molecular basis of the deletion, the mutant chromosomal PAH gene was isolated from this individual and shown to contain a GT--greater than AT substitution at the 5 splice donor site of intron 12.


Input: Thus, the consequence of the splice donor site mutation in the human liver is the skipping of the preceding exon during RNA splicing..


Input: Conservation of the Duchenne muscular dystrophy gene in mice and humans.

Duchenne muscular dystrophy


Input: A portion of the Duchenne muscular dystrophy (DMD) gene transcript from human fetal skeletal muscle and mouse adult heart was sequenced, representing approximately 25 percent of the total, 14-kb DMD transcript.

Duchenne muscular dystrophy

DMD

DMD


Input: The nucleic acid and predicted amino acid sequences from the two species are nearly 90 percent homologous.


Input: The amino acid sequence that is predicted from this portion of the DMD gene indicates that the protein product might serve a structural role in muscle, but the abundance and tissue distribution of the messenger RNA suggests that the DMD protein is not nebulin..

DMD

DMD


Input: Familial Prader-Willi syndrome with apparently normal chromosomes.

Prader-Willi syndrome


Input: We report on 4 sibs (2F, 2M) with Prader-Willi syndrome (PWS).

Prader-Willi syndrome

PWS


Input: Diagnosis was made clinically on the basis of history, behavior, and physical findings in 3 of the sibs.


Input: The other child had died at age 10 months with a history and clinical findings typical of first phase of PWS.

PWS


Input: Results of chromosome studies on the parents and surviving sibs were normal.


Input: The implications of this unusual familial occurrence for our understanding of PWS are discussed..

PWS


Input: Nebulin and titin expression in Duchenne muscular dystrophy appears normal.

Duchenne muscular dystrophy


Input: Monoclonal antibodies which recognize different epitopes on either titin or nebulin show normal staining patterns on frozen sections of three muscle biopsies of Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy

DMD


Input: Gel electrophoresis and immunoblotting performed on two of these muscle biopsies show the normal pattern of titin and nebulin polypeptides.


Input: Since the donor of one of these biopsies has a large deletion of the 5-region of the DMD gene, our results argue against the recent proposal that nebulin is the gene mutated in DMD..

DMD

DMD


Input: Heterozygous C2 deficiency associated with angioedema, myasthenia gravis, and systemic lupus erythematosus.

Heterozygous C2 deficiency

angioedema

myasthenia gravis

systemic lupus erythematosus


Input: We describe a patient with myasthenia gravis, systemic lupus erythematosus, and angioedema associated with heterozygous complement factor 2 (C2) deficiency.

myasthenia gravis

systemic lupus erythematosus

angioedema

complement factor 2 (C2) deficiency


Input: The significance of this association is controversial, though the association of C2 deficiency with certain histocompatibility antigens suggests possible linkage to immune response genes.

C2 deficiency


Input: To our knowledge this is the first report of heterozygous C2 deficiency in association with this combination of autoimmune disorders, and we discuss the aetiological implications..

C2 deficiency

autoimmune disorders


Input: Genetic analysis of an inherited deficiency of the third component of complement in Brittany spaniel dogs.

deficiency of the third component of complement


Input: Genetically determined C3 deficiency in Brittany spaniel dogs shares a number of biochemical and clinical characteristics with the human disorder.

C3 deficiency


Input: In humans, the gene for C3 deficiency is a null gene that is allelic to the structural gene for C3 and is not linked to the major histocompatibility locus.

C3 deficiency


Input: The current study used allotype analysis of canine C3 in order to demonstrate that the gene for C3 deficiency in these dogs is also a null gene allelic to the structural gene for C3.

C3 deficiency


Input: In addition, preliminary pedigree analysis suggests that the gene for canine C3 deficiency is apparently not closely linked to the major histocompatibility complex of the dog.

C3 deficiency


Input: Thus, it appears that C3 deficiency in Brittany spaniel dogs not only shares biochemical and clinical features with C3 deficiency in humans, but also shares some genetic characteristics with the human disorder..

C3 deficiency

C3 deficiency


Input: Gene transfer and expression of human phenylalanine hydroxylase.


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

Phenylketonuria

PKU

deficiency of the enzyme phenylalanine hydroxylase


Input: A full-length complementary DNA clone of human PAH was inserted into a eukaryotic expression vector and transferred into mouse NIH3T3 cells which do not normally express PAH.


Input: The transformed mouse cells expressed PAH messenger RNA, immunoreactive protein, and enzymatic activity that are characteristic of the normal human liver products, demonstrating that a single gene contains all of the necessary genetic information to code for functional PAH.


Input: These results support the use of the human PAH probe in prenatal diagnosis and detection of carriers, to provide new opportunities for the biochemical characterization of normal and mutant enzymes, and in the investigation of alternative genetic therapies for PKU..

PKU


Input: Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome.

phenylketonuria


Input: Phenylketonuria (PKU) is an autosomal recessive disorder of amino acid metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH; phenylalanine 4-monooxygenase, EC 1. 14. 16. 1).

Phenylketonuria

PKU

autosomal recessive disorder

deficiency of the hepatic enzyme phenylalanine hydroxylase


Input: A cDNA clone for human PAH has previously been used to assign the corresponding gene to human chromosome 12.


Input: To define the regional map position of the disease locus and the PAH gene on human chromosome 12, DNA was isolated from human-hamster somatic cell hybrids with various deletions of human chromosome 12 and was analyzed by Southern blot analysis using the human cDNA PAH clone as a hybridization probe.


Input: From these results, together with detailed biochemical and cytogenetic characterization of the hybrid cells, the region on chromosome 12 containing the human PAH gene has been defined as 12q14.


Input: 3----qter 3----qter.


Input: The PAH map position on chromosome 12 was further localized by in situ hybridization of 125I-labeled human PAH cDNA to chromosomes prepared from a human lymphoblastoid cell line.


Input: Results of these experiments demonstrated that the region on chromosome 12 containing the PAH gene and the PKU locus in man is 12q22----12q24.

PKU


Input: These results not only provide a regionalized map position for a major human disease locus but also can serve as a reference point for linkage analysis with other DNA markers on human chromosome 12


Input: Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor.

type I von Willebrand disease

von Willebrand


Input: Type I von Willebrand disease (vWD) is characterized by equally low plasma concentrations of von Willebrand factor antigen (vWF Ag) and ristocetin cofactor (RiCof) and by the presence of all vWF multimers in sodium dodecyl sulfate (SDS)-agarose gel electrophoresis.

Type I von Willebrand disease

vWD

von Willebrand


Input: For 17 patients (13 kindreds) diagnosed with these criteria, we have studied the platelet contents of vWF Ag and RiCof and the changes of these in plasma after DDAVP infusion.


Input: Platelet vWF Ag and RiCof were normal in four kindreds (called " platelet normal " subgroup); following 1-deamino-8-D-arginine vasopressin; plasma vWF Ag, RiCof and the bleeding time (BT) became normal.


Input: In six kindreds, platelet vWF Ag and RiCof were equally low (platelet low); after DDAVP, plasma vWF Ag and RiCof remained low, and the BT was prolonged.


Input: In three additional kindreds, platelets contained normal concentrations of vWF Ag, but RiCof was very low (platelet discordant); even though a complete set of multimers was found in plasma and platelets, there was a relatively small amount of large multimers.


Input: After DDAVP, plasma vWF Ag became normal, but RiCof remained low and the BT was very prolonged.


Input: These findings demonstrated that there can be an abnormal vWF (RiCof less than vWF Ag) even in type I vWD, coexisting with a complete set of vWF multimers (platelet discordant); that the abnormal vWF can be shown more clearly in platelets than in plasma or else in plasma after DDAVP infusion; and that DDAVP normalizes the BT only in those patients with normal platelet levels of both vWF Ag and RiCof (platelet normal)..

type I vWD


Input: Genetic analysis in families with van der Woude syndrome.

van der Woude syndrome


Input: We have brought together information on 864 affected individuals in 164 families (including three new pedigrees) reported in the 137 year period since 1845 when Demarquay first described a family with what was later called van der Woude syndrome (VWS).

van der Woude syndrome

VWS


Input: Both types of oral cleft, cleft palate (CP) and cleft lip with or without CP (CLP), segregate in these families together with lower lip pits or fistulae in an autosomal dominant mode with high penetrance estimated to be K =.

oral cleft

cleft palate

CP

cleft lip

CP

CLP

lip pits

fistulae


Input: 89 and.


Input: 99 by different methods.


Input: Cleft types (CLP and CP) occur in VWS in the same proportions as in the general non-VWS population, ie, about twice as many cleft-bearing individuals have CLP as have CP.

CLP

CP

VWS

CLP

CP


Input: On the other hand, we do not find the usually observed excess of females with CP and excess of males with CLP; in VWS the sex ratios are more nearly equal.

CP

CLP

VWS


Input: Lip pits also are equally distributed between the sexes.

Lip pits


Input: Affected males and females are equally likely to transmit VWS.

VWS


Input: However, there is an excess of less severely affected individuals among transmitters and a deficiency of more severely affected, brought about by a proband bias and differential fecundity.


Input: The expression of VWS is significantly modified by the genetic background More extreme phenotypes in parents tend to produce more extreme expression in their children.

VWS


Input: For a VWS gene carrier the relative risk of transmitting a cleft is 26.

VWS


Input: 45%; that of transmitting lower lip pits is 23.

lip pits


Input: Three pedigrees of lip pits in the literature show no clefts among a significant number of affected individuals.

lip pits


Input: Control of gene expression in VWS in the three target tissues appears to be independent and separately designated.

VWS


Input: Mutation rate of the VWS gene is calculated to be 1.

VWS


Input: 8 X 10 (-5)


Input: Hereditary C7 deficiency.

Hereditary C7 deficiency


Input: Diagnosis and HLA studies in a French-Canadian family.


Input: The serum of a 44-yr-old woman of French-Canadian descent having a B-27 positive ankylosing spondylitis was deficient in the seventh component of complement (C7) as determined by hemolytic and immunochemical methods.

ankylosing spondylitis

deficient in the seventh component of complement


Input: No inhibitor against C7 was detected, and the levels of all other complement components were normal.


Input: No deficiency in the opsonic activity of the serum was found, and the results of basic coagulation studies of the plasma were normal.


Input: On investigation of the patients family, two sisters were found to have the same deficiency but were otherwise in good health.


Input: The seven other siblings were heterozygous for C7 deficiency, while the paternal aunt had a normal C7 level.

C7 deficiency


Input: In the third generation, six children of the three homozygous sisters and five children of heterozygotes were available for testing.


Input: Studies of the HLA antigens in all the 22 subjects and in three spouses indicated no close linkage between the CM deficienty and the HLA system.

CM deficienty


Input: In addition, the simultaneous occurrence of two hereditary complement deficiencies (C2 and C7) was discovered in one family of this remarkable kindred..

complement deficiencies (C2 and C7)


Input: Genetic defect in secretion of complement C5 in mice.

defect in secretion of complement C5


Input: A genetic deficiency of the fifth (C5) component of complement1-3, a serum glycoprotein of molecular weight (MW) 220, 000 (ref. 4), has been found in 39% of inbred strains of mice3.

deficiency of the fifth (C5) component of complement1-3


Input: Sera of deficient mice lack detectable C5 activity and protein2, 3.


Input: In addition deficient mice produce antibody to mouse C5 when injected with sera from C5 sufficient (normal) strains.


Input: Levy et al.


Input: 5 showed that somatic cell hybrids between C5 deficient (B10. D2/old line) macrophages and either C5 sufficient (B10. D2/new line) mouse kidney or chicken erythroblasts secreted haemolytically active mouse C5 in vitro.


Input: Several possible molecular mechanisms to account for the findings were considered, but insufficient direct data were available to choose among them.


Input: We recently reported that mouse (CD. 1 strain) peritoneal cells in culture synthesise and secrete a single chain precursor, pro-C5 (MW approximately 210, 000), of the two-chain (alpha chain, 125, 000 and beta chain 83, 000 MW) C5 protein6.


Input: Radiolabelled precursor C5 was contained within the cells and was secreted into the tissue culture media.


Input: Using similar methods, we now find that C5 deficiency in each of five different mouse strains (AKR, SWR, DBA/2J8 A/HeJ and B10. D2/old line) is due to a failure in secretion of C5 protein and not to a failure in biosynthesis of pro-C5

C5 deficiency


Input: Recurrent meningococcal meningitis with absence of the sixth component of complement: an evaluation of underlying immunologic mechanisms.

meningococcal meningitis

absence of the sixth component of complement


Input: A 51/2-year-old black girl with recurrent meningococcal meningitis and absence of the sixth component of complement (C6) is reported.

meningococcal meningitis

absence of the sixth component of complement


Input: To explore the pathogenesis of recurrent neisserial infections in C6 deficiency, a detailed analysis of her immune competence was conducted.

neisserial infections

C6 deficiency


Input: Her serum had normal chemotactic, opsonic, alternative complement pathway, and specific antibody activity, but lacked complement-mediated bacteriolytic activity.


Input: In addition, her C6-deficient serum was indistinguishable from normal serum in a complement-dependent assay of phagocyte bactericidal activity.


Input: Absent bacteriolysis remains the only consistent defect associated with recurrent neisserial infections and absence of one of the late-acting complement components..

neisserial infections


Input: Deficiency of the fifth component of complement in human subjects.

Deficiency of the fifth component of complement


Input: Clinical, genetic and immunologic studies in a large kindred.


Input: The discovery of a large kindred with a heritable deficiency of the fifth component of complement (C5) has permitted the accumulation of new clinical, genetic and immunologic data concerning the role of C5 in human subjects.

deficiency of the fifth component of complement


Input: The proband, who has had nine episodes of disseminated gonococcal infection, has a hemolytic C5 level of approximately 0.

gonococcal infection


Input: 5 per cent of normal.


Input: No C5 protein was detectable, but low levels of functional C5 activity could be found using a sensitive bactericidal assay.


Input: The probands twin as well as another sister also had extremely low levels of hemolytic C5 (approximately 0. 5 per cent normal), but both these subjects have been healthy.


Input: Hemolytic complement and bacteriolytic activity could be restored by the addition of purified C5.


Input: No chemotactic activity for polymorphonuclear leukocytes could be generated in the C5-deficient serums upon activation of either the classic or alternative pathways, again demonstrating the importance of C5 in human subjects for the production of chemotactic factors.


Input: The chemotactic responsiveness of the patients polymorphonuclear leukocytes and monocytes to preformed chemotactic factors was not depressed.


Input: Twenty-two of 32 other family members from three generations had depressed whole hemolytic complement levels.


Input: In 19 of 30 family members, levels of hemolytic C5 ranged from 13 to 64 per cent of normal.


Input: No linkage for C5 deficiency and the A or B loci of the major histocompatibility complex could be found.

C5 deficiency


Input: These data suggest an autosomal codominant mode of inheritance of C5 deficiency.

C5 deficiency


Input: Deficiency of C5 is compatible with good health, but it can be associated with repeated disseminated gonococcal infection

Deficiency of C5


Input: Incidence and characteristics of glucose-6-phosphate dehydrogenase variants in Japan.


Input: A total of 3000 men living in Yamaguchi were screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency using Beutlers spot test and three types of starch gel electrophoresis.

glucose-6-phosphate dehydrogenase (G6PD) deficiency


Input: These electrophoresis used a phosphate buffer system at pH 7.


Input: 0, a TRIS-EDTA-borate buffer system at pH 8.


Input: 6, and a TRIS-hydrochloride buffer system at pH 8..


Input: Fifteen G6PD-deficient variants were found at the rate of 0.


Input: 5% and classified into four groups.


Input: As new variants, G6PD Konan, Kamiube, and Kiwa were identified.


Input: These three variants had a mild to moderate G6PD deficiency and were not associated with any clinical signs.

G6PD deficiency


Input: G6PD Konan had fast electrophoretic mobility as compared with normal levels, G6PD Kiwa had slightly elevated electrophoretic mobility, and G6PD Kamiube had normal electrophoretic mobility.


Input: These three variants had normal levels of Km G6P, Km NADP, and Ki NADPH, normal utilizations of both 2-deoxy-G6P and deamino-NAPD, normal heat stability, and a normal pH curve.


Input: The other variant was G6PD Ube, which we had previously found in Yamaguchi (Nakashima et al., 1977).


Input: One boy with G6PD Ube was Korean


Input: Utilization of purines by an HPRT variant in an intelligent, nonmutilative patient with features of the Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome


Input: The patient, H.


Input: Chr.


Input: B., was among the first reported with hyperuricemia and central nervous system symptoms.

hyperuricemia

central nervous system symptoms


Input: He has been found to have a variant of hypoxanthine guanine phosphoribosyl transferase (HPRT; E. C. 2. 4. 2. 8) distinct from the enzyme present in patients with the Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome


Input: The patient had chroeoathetosis, spasticity, dysarthric speech, and hyperuricemia.

chroeoathetosis

spasticity

dysarthric speech

hyperuricemia


Input: However, his intelligence was normal and he had no evidence of self-mutilation.


Input: There was no activity of HPRT in the lysates of erythrocytes and cultured fibroblasts when analyzed in the usual manner.


Input: Using a newly developed method for the study of purine metabolism in intact cultured cells, this patient was found to metabolize some 9% of 8-14C-hypoxanthine, and 90% of the isotope utilized was converted to adenine and guanine nucleotides.


Input: In contrast, cells from patients with the Lesch-Nyhan syndrome were virtually completely unable to convert hypoxanthine to nucleotides.

Lesch-Nyhan syndrome


Input: The patients fibroblasts were even more efficient in the metabolism of 8-14C-guanine, which was utilized to the extent of 27%, over 80% of which was converted to guanine and adenine nucleotides.


Input: The growth of the cultured fibroblasts of this patient was intermediate in media containing hypoxanthine aminopterin thymidine (HAT), whereas the growth of Lesch-Nyhan cells was inhibited and normal cells grew normally.

Lesch-Nyhan


Input: Similarly in 8-azaguanine, 6-thioguanine, and 8-azahypoxanthine, the growth of the patients cells was intermediate between normal and Lesch-Nyhan cells.

Lesch-Nyhan


Input: These observations provide further evidence for genetic heterogeneity among patients with disorders in purine metabolism involving the HPRT gene.


Input: They document that this famous patient did not have the Lesch-Nyhan syndrome


Input: Localisation of the Becker muscular dystrophy gene on the short arm of the X chromosome by linkage to cloned DNA sequences.

Becker muscular dystrophy


Input: A linkage study in 30 Becker muscular dystrophy (BMD) kindreds using three cloned DNA sequences from the X chromosome which demonstrate restriction fragment length polymorphisms (RFLPs), suggests that the BMD gene is located on the short arm of the X chromosome, in the p21 region.

Becker muscular dystrophy

BMD

BMD


Input: The genes for Becker and Duchenne dystrophies must therefore be closely linked, if not allelic, and any future DNA probes found to be of practical use in one disorder should be equally applicable to the other.

Becker and Duchenne dystrophies


Input: The linkage analysis also provides data on the frequency of recombination along the short arm of the X chromosome, and across the centromeric region..


Input: Molecular evidence for new mutation at the hprt locus in Lesch-Nyhan patients.

Lesch-Nyhan


Input: Hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC2. 4. 2. 8), which functions in the metabolic salvage of purines, is encoded by an X-linked gene in man.


Input: Partial HPRT deficiencies are associated with gouty arthritis, while absence of activity results in Lesch-Nyhan syndrome (L-N).

HPRT deficiencies

gouty arthritis

Lesch-Nyhan syndrome

L-N


Input: L-N patients fail to reproduce and the heterozygous state appears to confer no selective advantage.

L-N


Input: Thus, Haldanes principle predicts that new mutations at the hprt locus must occur frequently in order for L-N syndrome to be maintained in the population.

L-N syndrome


Input: This constant introduction of new mutations would be expected to result in a heterogeneous collection of genetic lesions, some of which may be novel.

genetic lesions


Input: As we report here, the mutations in the hprt gene of seven L-N patients, selected from an initial survey of 28 patients, have been characterized and all were found to be distinctly different, as predicted.

L-N


Input: The origin of one unusual mutation has been identified by analysis of DNA from four generations of family members.


Input: Further molecular analysis of the origin of new mutations at the hprt locus should aid in resolving the issue of an apparent difference in the frequency of hprt mutations in males and females


Input: Allelic exclusion of glucose-6-phosphate dehydrogenase in platelets and T lymphocytes from a Wiskott-Aldrich syndrome carrier.

Wiskott-Aldrich syndrome


Input: An obligate carrier of the Wiskott-Aldrich syndrome (WAS) who was also heterozygous for the A and B types of X-linked glucose-6-phosphate dehydrogenase was found.

Wiskott-Aldrich syndrome

WAS


Input: With her it became possible to determine whether allelic exclusion occurs in particular cell-types of the WAS carrier.

WAS


Input: If so, the remaining cells of a particular cell-type would express only the normal X chromosome and only one glucose-6-phosphate dehydrogenase isoenzyme would be demonstrable.


Input: This carrier had only the B isoenzyme of glucose-6-phosphate dehydrogenase in platelets and thymus-derived T lymphocytes, although both isoenzymes A and B were present in erythrocytes and neutrophils.


Input: These findings suggest that selection against the WAS gene occurs in platelets and thymus-derived T lymphocytes and that the defects associated with WAS expressed in these cell-types may be implicated in the genesis of the Wiskott-Aldrich syndrome..

WAS

WAS

Wiskott-Aldrich syndrome


Input: Complement deficiency and nephritis.

Complement deficiency

nephritis


Input: A report of a family.


Input: A family is described in which three children had homozygous deficiency of C3 and in which both parents and two other children were heterozygous for the C3 null gene.

deficiency of C3


Input: One child with heterozygous C3 deficiency was found to have membranoproliferative glomerulonephritis; proteinuria and/or microscopical haematuria was present in all three homozygous C3-deficient children.

C3 deficiency

glomerulonephritis

proteinuria

haematuria


Input: All children with homozygous or heterozygous C3 deficiency were, to a varying degree, susceptible to infection.

C3 deficiency


Input: The only child of the family with normal complement had no increased risk of infection and no renal disease.

renal disease


Input: This family study provides further support for the proposal that C3 deficiency predisposes to nephritis..

C3 deficiency

nephritis


Input: Heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Algeria.

glucose-6-phosphate dehydrogenase deficiency


Input: Study in Northern Algeria with description of five new variants.


Input: Glucose-6-phosphate dehydrogenase (G6PD) deficiency was found in 3.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency


Input: 2% of the male population living in the urban area of Algiers.


Input: The deficient subjects originated from multiple geographic regions of Northern Algeria, with prevalence of individuals of Berber-Kabyle origin.


Input: Red blood cell G6PD was partially purified and characterized in deficient males from 17 families, and six different variants were found.


Input: Among them, only one, the Gd (-) Kabyle variant, had been previously described.


Input: It was detected in nine families.


Input: The other five variants were new Gd (-) Laghouat (four cases), Gd (-) Blida (one case), Gd (-) Thenia (one case), Gd (-) Titteri (one case), and Gd (-) Alger (two brothers).


Input: Strikingly, the common Mediterranean variant was not found.


Input: G6PD deficiency is heterogeneous in northern Algeria where autochtonous variants seem to prevail.

G6PD deficiency


Input: The Kabyle variant may be common in this country.


Input: Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro growth of Plasmodium falciparum.

Glucose-6-phosphate dehydrogenase deficiency


Input: Glucose-6-phosphate dehydrogenase (G6PD; EC 1. 1. 1. 49)-deficient red blood cells from male hemizygotes and female heterozygotes from the island of Sardinia were studied for their ability to support growth in vitro of the malaria-causing organism Plasmodium falciparum.

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

malaria


Input: Parasite growth was approximately one-third of normal in both hemi-and heterozygotes for G6PD deficiency.

G6PD deficiency


Input: In Sardinians with the beta 0-thalassemia trait, parasite growth was normal except when G6PD deficiency occurred together with the thalassemia trait.

G6PD deficiency

thalassemia


Input: The data support the hypothesis that G6PD deficiency may confer a selective advantage in a malarious area; the female heterozygote may be at a particular advantage because resistance to malaria equals that of male hemizygotes, but the risk of fatal hemolysis may be less.

G6PD deficiency

malarious

malaria

fatal hemolysis


Input: However, more female heterozygotes must be studied to confirm this hypothesis.


Input: No protective effect of beta 0-thalassemia trait could be demonstrated in vitro.


Input: Bone marrow transplant in adrenoleukodystrophy.

adrenoleukodystrophy


Input: An allogeneic bone marrow transplant (BMT) from a normal HLA identical sibling donor was performed in a 13-year-old boy with rapidly progressive adrenoleukodystrophy (ALD).

adrenoleukodystrophy

ALD


Input: Engraftment and complete hematologic recovery occurred within 4 weeks, but neurologic deterioration continued.

neurologic deterioration


Input: The patient died of an adenovirus infection 141 days after BMT.

adenovirus infection


Input: ALD is characterized by abnormally high plasma levels of very long chain fatty acids (VLCFA) as a result of impaired capacity to degrade them.

ALD


Input: Ten days after BMT, the white blood cell VLCFA levels and enzyme activity became normal; after 3 months, there was progressive reduction of plasma VLCFA to levels only slightly above normal..


Input: [Gd-allele distribution patterns in Azerbaijan. III. The identification of mutant forms of glucose-6-phosphate dehydrogenase]


Input: In 28 families with G6PD deficiency living in 3 settlements of Shekii district of Azerbaijan 11 G6PD variants of II and III classes differing by kinetic properties were identified according WHO program.

G6PD deficiency


Input: 9 of them are characterized with the same electrophoretic mobility.


Input: Comparison of G6PD spectra in two subpopulations and in a mixed group permits to make a conclusion about existence of common and rare G6PD alleles in examined population.


Input: They distribute by gene drift supported by natural selection.


Input: Among 7 samples of G6PD with normal and increased activity two new variants of IV class--Nukha and Bash-Kungut--were found..


Input: Adrenoleukodystrophy: survey of 303 cases: biochemistry, diagnosis, and therapy.

Adrenoleukodystrophy


Input: Adrenoleukodystrophy (ALD) is a genetically determined disorder associated with progressive central demyelination and adrenal cortical insufficiency.

Adrenoleukodystrophy

ALD

progressive central demyelination

adrenal cortical insufficiency


Input: All affected persons show increased levels of saturated unbranched very-long-chain fatty acids, particularly hexacosanoate (C26 0), because of impaired capacity to degrade these acids.


Input: This degradation normally takes place in a subcellular organelle called the peroxisome, and ALD, together with Zellwegers cerebrohepatorenal syndrome, is now considered to belong to the newly formed category of peroxisomal disorders.

ALD

Zellwegers cerebrohepatorenal syndrome

peroxisomal disorders


Input: Biochemical assays permit prenatal diagnosis, as well as identification of most heterozygotes.


Input: We have identified 303 patients with ALD in 217 kindreds.

ALD


Input: These patients show a wide phenotypic variation.


Input: Sixty percent of patients had childhood ALD and 17% adrenomyeloneuropathy, both of which are X-linked, with the gene mapped to Xq28.

ALD

adrenomyeloneuropathy


Input: Neonatal ALD, a distinct entity with autosomal recessive inheritance and points of resemblance to Zellwegers syndrome, accounted for 7% of the cases.

Neonatal ALD

Zellwegers syndrome


Input: Although excess C26 0 in the brain of patients with ALD is partially of dietary origin, dietary C26 0 restriction did not produce clear benefit.

ALD


Input: Bone marrow transplant lowered the plasma C26 0 level but failed to arrest neurological progression..


Input: Genetic polymorphism of G6PD in a Bulgarian population.


Input: Considerable genetic heterogeneity in G6PD was found in the Bulgarian population-14 G6PD variants isolated from 117 hemizygous carriers of G6PD deficiency.

G6PD deficiency


Input: Of these, G6PD Mediterranean type was a polymorphic variant and G6PD Corinth occurred with high frequency.


Input: Two new variants were identified-G6PD Rudosem and G6PD Nedelino.


Input: In a selected group of 78 subjects with clinical manifestations, four variants were established G6PD Mediterranian, G6PD Corinth, G6PD Seattle and G6PD Ohut II..


Input: Clinical use of DNA markers linked to the gene for Duchenne muscular dystrophy.

Duchenne muscular dystrophy


Input: Seventy families with Duchenne muscular dystrophy (DMD) known to the Institute of Child Health fall into three categories with respect to potential linkage analysis with the X chromosome DNA markers RC8 and L1.

Duchenne muscular dystrophy

DMD


Input: 28 that bridge the DMD gene.

DMD


Input: Families in which there is at least one obligatory female heterozygote (n = 13).


Input: Here prediction and exclusion of DMD gene transmission may be possible, the accuracy being dependent on the closeness of the linkage of the DNA marker (s) to the DMD gene; an illustrative case is reported.

DMD

DMD


Input: Families in which there is a single affected boy, who also has one or more healthy brothers (n = 26).


Input: Given an informative restriction fragment length polymorphism (RFLP), the probability that the boy represents a new mutation can be reassessed; it is also possible to exclude the DMD gene in a sister.

DMD


Input: Families with a single affected boy with no brother (n = 30).


Input: Here exclusion of the DMD gene in a sister may be possible.

DMD


Input: Only in one family was there no possibility of useful linkage analysis.


Input: The linkage analysis required is described, and the need to check DMD families for informative RFLPs is stressed.

DMD


Input: Family studies in Bechterew' s syndrome (ankylosing spondylitis) III.

Bechterew' s syndrome

ankylosing spondylitis


Input: Genetics.


Input: The results of segregation analyses in 75 families where the proband had ankylosing spondylitis, are presented.

ankylosing spondylitis


Input: Of the 278 adult, living first degree relatives, approximately 85% cooperated in the study.


Input: Clinical and radiographical examinations were performed and HLA typing was conducted.


Input: The results were in agreement with our hypothesis that ankylosing spondylitis is part of a syndrome where different genetic factors interact.

ankylosing spondylitis


Input: Such known factors are HLA B27 associated disease susceptibility, susceptibility to psoriatic arthropathy and susceptibility to entero-arthropathy.

psoriatic arthropathy

entero-arthropathy


Input: Radiographical sacro-iliitis was restricted to HLA B27 positive relatives, and was more frequently found in relatives to probands with psoriasis than in relatives to probands without psoriasis.

sacro-iliitis

psoriasis

psoriasis


Input: Environmental factors (intestinal bacteria) are known to trigger the disease at least in some persons, and we have postulated that all or most of them have the predisposition to develop disease.


Input: Thus, the syndrome has a multifactorial etiology.


Input: The phenotypic expressions of the different genetic predispositions involved, include sacro-iliitis, psoriasis, acute anterior uveitis, peripheral arthropathy and inflammatory bowel disease.

sacro-iliitis

psoriasis

acute anterior uveitis

arthropathy

inflammatory bowel disease


Input: We suggest the descriptive name HEREDITARY MULTIFOCAL RELAPSING INFLAMMATION (HEMRI) for this syndrome.

HEREDITARY MULTIFOCAL RELAPSING INFLAMMATION

HEMRI


Input: Ankylosing spondylitis, psoriatic arthropathy and entero-arthropathy may be regarded as clinical sub-types of the syndrome..

Ankylosing spondylitis

psoriatic arthropathy

entero-arthropathy


Input: Prader-Willi syndrome and chromosome 15.

Prader-Willi syndrome


Input: A clinical discussion of 20 cases.


Input: A chromosome 15 anomaly was observed in 12 of 20 patients, 17 of whom were clinically suspected of having Prader-Willi syndrome (PWS).

chromosome 15 anomaly

Prader-Willi syndrome

PWS


Input: The clinical features of eight cases with 15q11-12 deletion were very similar to those originally described in PWS.

PWS


Input: On the other hand, the group of normal karyotype patients is heterogeneous, and their features do not strictly correspond to the clinical definition of PWS.

PWS


Input: However, the hypothesis that PWS is associated with deletion of 15q11-12 can neither explain the apparently balanced translocations of chromosome 15 nor account for the small supernumerary metacentric chromosomes corresponding to an isochromosome 15 for band 15q11 observed in some cases..

PWS


Input: The Tay-Sachs disease gene in North American Jewish populations: geographic variations and origin.

Tay-Sachs disease


Input: From data collected in a North American Tay-Sachs disease (TSD) heterozygote screening program, the TSD carrier frequency among 46, 304 Jewish individuals was found to be.

Tay-Sachs disease

TSD

TSD


Input: 0324 (1 in 31 individuals).


Input: This frequency is consistent with earlier estimates based on TSD incidence data.

TSD


Input: TSD carrier frequencies were then examined by single country and single region of origin in 28, 029 Jews within this sample for whom such data were available for analysis.

TSD


Input: Jews with Polish and/or Russian ancestry constituted 88% of this sample and had a TSD carrier frequency of.

TSD


Input: No TSD carriers were observed among the 166 Jews of Near Eastern origins.

TSD


Input: Relative to Jews of Polish and Russian origins, there was at least a twofold increase in the TSD carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins (P less than. 005).

TSD


Input: These findings suggest that the TSD gene proliferated among the antecedents of modern Ashkenazi Jewry after the Second Diaspora (70 A. D.) and before their major migrations to regions of Poland and Russia (before 1100 A. D.).

TSD


Input: Human deficiency of the sixth component of complement in a patient with meningococcal meningitis and no haemostasis abnormality.

deficiency of the sixth component of complement

meningococcal meningitis

haemostasis abnormality


Input: A case of human complete C6 deficiency is reported.

C6 deficiency


Input: The patient, a 31 year old white male, was seen on the occasion of an isolated episode of meningococcal meningitis.

meningococcal meningitis


Input: Serum complement hemolytic and bactericidal activities were lacking and could be restored to normal by addition of appropriate amounts of purified C6.


Input: No hemostatic abnormalities were observed..

hemostatic abnormalities


Input: Absence of the seventh component of complement in a patient with chronic meningococcemia presenting as vasculitis.

Absence of the seventh component of complement

chronic meningococcemia

vasculitis


Input: A previously healthy 40-year-old man presenting with fever, arthritis, and cutaneous vasculitis was found to have chronic meningococcemia.

fever

arthritis

cutaneous vasculitis

chronic meningococcemia


Input: Evaluation of his complement system showed an absence of functional and antigenic C7, compatible with a complete deficiency of the seventh component of complement.

deficiency of the seventh component of complement


Input: Study of the patients family spanning four generations showed heterozygous deficiency of C7 in five members.

deficiency of C7


Input: Chronic neisserial infection can be associated with C7 deficiency and must be distinguished from other causes of cutaneous vasculitis..

Chronic neisserial infection

C7 deficiency

cutaneous vasculitis


Input: Familial discoid lupus erythematosus associated with heterozygote C2 deficiency.

Familial discoid lupus erythematosus

C2 deficiency


Input: Two siblings with chronic discoid lupus erythematosus and several family members were found with heterozygous C2 deficiency.

chronic discoid lupus erythematosus

C2 deficiency


Input: An association with histocompatibility markers HLA-B18 and HLA-Dw2 was demonstrated, and the slow allotype of factor B was present.


Input: Linkage studies in this family suggested a close linkage between the C2 deficiency gene and genes coding for B18, Dw2, and BfS antigens.

C2 deficiency


Input: One HLA-ACB/DBf recombinant was observed showing closer linkage between HLA-D and Bf than between HLA-B and Bf..


Input: Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with chronic hemolytic anemia, granulocyte dysfunction, and increased susceptibility to infections: description of a new molecular variant (G6PD Barcelona).

Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency

hemolytic anemia

granulocyte dysfunction


Input: Molecular, kinetic, and functional studies were carried out on erythrocytes and leukocytes in a Spanish male with G6PD deficiency, congenital nonspherocytic hemolytic anemia (CNSHA), and increased susceptibility to infections.

G6PD deficiency

congenital nonspherocytic hemolytic anemia

CNSHA


Input: G6PD activity was absent in patients red cells and was about 2% of normal in leukocytes.


Input: Molecular studies using standard methods (WHO, 1967) showed G6PD in the patient to have a slightly fast electrophoretic mobility at pH 8.


Input: 0 with otherwise normal properties (heat stability at 46 degrees C, apparent affinity for substrates, optimum pH, and utilization of substrate analogues).


Input: Other tests showed the patients granulocytes to engulf latex particles normally, but to have impaired reduction of nitroblue tetrazolium and ferricytochrome-c as well as reduced iodination.


Input: Chemotaxis and random migration of the patients granulocytes were normal as were myeloperoxidase, leukocyte alkaline phosphatase (LAP), and ultrastructural features.


Input: The molecular characteristics of G6PD in the patient differed from those of all previously reported variants associated with CNSHA, so the present variant was provisionally called G6PD Barcelona to distinguish it from other G6PD variants previously described.

CNSHA


Input: Possible mechanisms for the severe deficiency of G6PD in erythrocytes and granulocytes was investigated by studies on the immunologic specific activity of the mutant enzyme.

deficiency of G6PD


Input: Glucose-6-phosphate dehydrogenase deficiency in Papua New Guinea.

Glucose-6-phosphate dehydrogenase deficiency


Input: The description of 13 new variants.


Input: A total of 362 males from various regions of Papua New Guinea were screened for red cell glucose-6-phosphate dehydrogenase (G6PD) activity.


Input: Twenty-six G6PD deficient individuals were identified.

G6PD deficient


Input: Biochemical characterization of G6PD purified from these subjects has revealed 13 new variants and several copies of previously described forms of G6PD.


Input: This study illustrates the extreme heterogeneity of G6PD deficiency among the people of Papua New Guinea..

G6PD deficiency


Input: Heterogeneity of " Mediterranean type " glucose-6-phosphate dehydrogenase (G6PD) deficiency in Spain and description of two new variants associated with favism.

glucose-6-phosphate dehydrogenase (G6PD) deficiency

favism


Input: Glucose-6-phosphate dehydrogenase (G6PD); EC 1.


Input: 49 from thirty-six unrelated Spanish males was partially purified from blood, and the variants were characterized biochemically and electrophoretically according to the methods recommended by the world Health Organization.


Input: Subjects were from multiple geographic regions within Spain, and all suffered from hemolytic anemia, either acute (34 cases) or chronic nonspherocytic (2 cases).

hemolytic anemia


Input: Almost all the variants studied presented residual erythrocyte G6PD activity ranging from 0 to 10% of normal, and five different mutants were responsible for the deficient phenotype.


Input: Three variants were similar to others previously described G6PD Mediterranean (11 cases), G6PD Athens-like (3 cases), and G6PD Union (2 cases).


Input: The remaining variants were different from the numerous variants already reported and have been considered as new mutants.


Input: Provisionally they are called G6PD Betica (19 cases) and G6PD Menorca (1 case).


Input: The present study constitutes the first attempt to characterize the deficient G6PD variants found in Spain and supplies new data on the relationship between molecular characteristics of deficient variants and their clinical manifestations.

deficient G6PD


Input: The most important findings can be summarized as follows (1) The Spanish population is characterized by an important heterogeneity in G6PD deficiency.

G6PD deficiency


Input: (2) Although G6PD Mediterranean is very frequent, it presents a relatively high degree of polymorphism.


Input: (3) Favism has been observed associated with all kinds of variants described here.

Favism


Input: (4) G6PD Betica, which is the most frequent variant found in subjects of Southern Spanish origin, has been observed associated with favism in all cases except one.

favism


Input: A new glucose-6-phosphate dehydrogenase variant (G6PD Nagano) associated with congenital hemolytic anemia.

congenital hemolytic anemia


Input: A new glucose-6-phosphate dehydrogenase (G6PD) variant associated with chronic nonspherocytic hemolytic anemia was reported.

chronic nonspherocytic hemolytic anemia


Input: The patient, a 6-year-old Japanese male, was noticed to have hemolytic anemia soon after birth, and a diagnosis of G6PD deficiency was made at the age of 2.

hemolytic anemia

G6PD deficiency


Input: He had episodes of hemolytic crisis several times after upper respiratory infection.

hemolytic crisis

upper respiratory infection


Input: G6PD activity of the patient was 5.


Input: 5% of normal.


Input: The enzymatic characteristics were examined when he was 5 years old, and his G6PD showed faster-than-normal electrophoretic mobility, low Km G6P, high Km NADP, low Ki NADPH, normal utilization of substrate analogues, heat instability, and a normal pH optimum curve.


Input: From these results, this was considered to be a new variant and was designated G6PD Nagano.


Input: Infection-induced hemolysis and chronic hemolytic anemia seem to be due to markedly impaired enzyme activity and thermal instability.

hemolysis

chronic hemolytic anemia


Input: Heterozygous C2-deficiency and myasthenia gravis.

myasthenia gravis


Input: Complement deficiency states in myasthenia gravis (MG) have not been reported previously.

Complement deficiency

myasthenia gravis

MG


Input: We describe a 19-year-old woman with typical MG and heterozygous C2 deficiency, along with HLA typing of the patient and her immediate family..

MG

C2 deficiency


Input: Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.

Adrenoleukodystrophy


Input: With a new method we measured the saturated very long chain fatty acids in the plasma of adrenoleukodystrophy (ALD) hemizygotes, ALD heterozygotes, and controls.

adrenoleukodystrophy

ALD

ALD


Input: ALD hemizygotes showed increased levels of hexacosanoate (C26 fatty acid) which represented 0.

ALD


Input: 081 +/-0.


Input: 0066% (SEM) of total fatty acids, compared to 0.


Input: 015 +/-0.


Input: 0032% in the controls.


Input: C25, C24, and C23 fatty acids were also increased, but the C22 and C20 fatty acids were normal.


Input: C26 levels were also increased in most ALD heterozygotes, with a mean level 0.

ALD


Input: 057 +/-0.


Input: 0063% of total fatty acids.


Input: The technique can be used for diagnosis and carrier identification, and in the evaluation of therapy.


Input: Abnormal high density lipoproteins in cerebrotendinous xanthomatosis.

cerebrotendinous xanthomatosis


Input: The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX).

genetic disease cerebrotendinous xanthomatosis

CTX


Input: Abnormalities in the HDL may contribute to their increased atherogenesis and excessive deposits of tissue sterols in the presence of low or low-normal concentrations of plasma cholesterol (165 +/-25 mg/dl) and low density lipoproteins (LDL).

Abnormalities in the HDL


Input: The mean HDL-cholesterol concentration in the CTX plasmas was 14.

CTX


Input: 5 +/-3.


Input: 2 mg/dl, about one-third the normal value.


Input: The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL.


Input: Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased.


Input: The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal.

CTX


Input: In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms.

CTX


Input: The HDL in electron micrographs appeared normal morphologically and in particle size.


Input: The abnormalities in lipoprotein distribution profile and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX.

genetic defect

CTX


Input: As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease.


Input: Genetics of cerebrotendinous xanthomatosis (CTX): an autosomal recessive trait with high gene frequency in Sephardim of Moroccan origin.

cerebrotendinous xanthomatosis

CTX


Input: We described 6 patients (from 3 families) affected with cerebrotendinous xanthomatosis (CTX).

cerebrotendinous xanthomatosis

CTX


Input: All are Sephardic Jews of Moroccan extraction.


Input: In view of the small number of CTX patients diagnosed in the world (a total of 50 including our 6 patients), we are probably dealing with an ethnic subgroup with a high CTX gene frequency, which we have estimated to be 1/108.

CTX


Input: Since there are differences in expression in this disease, we recommend cholestanol study in cases of undiagnosed cataract or tendinous xanthomas in childhood or early adolescence.

cataract

tendinous xanthomas


Input: The diagnosis in CTX is important not only for genetic counseling, but also in veiw of possible treatment..

CTX


Input: New genetic variants of glucose 6-phosphate dehydrogenase (G6PD) in Italy.


Input: Six new variants of human erythrocyte G6PD have been characterized.


Input: All of them were found in Italian males and all were associated with enzyme deficiency, but only two with signs of haemolysis.

enzyme deficiency

haemolysis


Input: These and other variants reported in the literature, which must thus far be regarded as sporadic, are found to map in parts of Italy where common types of G6PD deficiency are also prevalent..

G6PD deficiency


Input: Variants of erythrocyte glucose-6-phosphate dehydrogenase (G6PD) in Bulgarian populations.


Input: Ten variants of erythrocyte glucose-6-phosphate dehydrogenase were identified in 22 patients with G6PD deficiency from three districts of Bulgaria.

G6PD deficiency


Input: Corinth-like and Fayoum-like variants were the most frequent; Mediterranean, Ohut II, Kilgore, Boston, Poznan, and Panay variants and two new variants, Petrich and Gotze Delchev, were each found in one or two carriers.


Input: No correlation was revealed between clinical and biochemical polymorphism..


Input: Nephropathy in the Wiskott-Aldrich syndrome.

Nephropathy

Wiskott-Aldrich syndrome


Input: Nephropathy was detected in five of 32 patients with the Wiskott-Aldrich syndrome who were participating in a study of transfer factor (TF) therapy.

Nephropathy

Wiskott-Aldrich syndrome


Input: In two patients, nephropathy was present before TF and did not appear changed by TF therapy.

nephropathy


Input: One of these patients subsequently developed progressive renal failure requiring dialysis beginning 5 1/2 years after TF therapy.

renal failure


Input: In two patients, decreased renal function appeared very soon after the administration of TF.


Input: One patient showed gradually decreasing renal function beginning after two years of TF therapy.


Input: An additional patient was identified who died with renal failure without having received TF.

renal failure


Input: The results suggest that renal failure occurs in the Wiskott-Aldrich syndrome more frequently than generally recognized and that administration of TF may precipitate or accelerate the renal disease in patients with this syndrome..

renal failure

Wiskott-Aldrich syndrome

renal disease


Input: Wiskott-Aldrich syndrome: cellular impairments and their implication for carrier detection.

Wiskott-Aldrich syndrome


Input: A family in which two male siblings were affected with Wiskott-Aldrich syndrome (WAS) was studied using G-6-PD isoenzymes as an X-linked marker in order to investigate the nature of cellular abnormalities.

Wiskott-Aldrich syndrome

WAS


Input: Isolated peripheral blood cell types from the doubly heterozygous mother of the affected males seemingly failed to express the G-6-PD allele in cis position with the WAS allele while her cultured skin fibroblasts expressed both G-6-PD alleles.

WAS


Input: Additionally, a histogram analysis of platelet size revealed a single population of abnormally small platelets in the affected propositus, whereas the heterozygous mother had no appreciable small platelet subpopulation.


Input: In vitro culture of hemopoietic progenitor cells of the heterozygous mother showed that the majority of progenitor cells did not express the WAS allele.

WAS


Input: However, a small number of cells expressing the G-6-PD type linked with the WAS allele were detected.

WAS


Input: The proportion of the latter progenitors was significantly higher among more primitive progenitors (those giving rise to later appearing colonies).


Input: This observation suggests that selection against cells expressing the Wiskott-Aldrich defect takes place in the hemopoietic system of the heterozygous female and offers a possible means of carrier detection in some women.

Wiskott-Aldrich defect


Input: Linkage studies in this family revealed one example of probable recombination between the loci for WAS and G-6-PD among three informative subjects, suggesting that these two loci may not be closely linked on the X-chromosome..

WAS


Input: A new CT pattern in adrenoleukodystrophy.

adrenoleukodystrophy


Input: A new CT pattern was observed in 2 patients with adrenoleukodystrophy (ALD).

adrenoleukodystrophy

ALD


Input: This pattern, which the authors call Type II, is characterized by the absence of posterior periventricular areas of decreased attenuation around the trigone on non-contrast scans after contrast infusion, however, there is striking enhancement of various white-matter structures (tracts or fiber systems) such as the internal capsules, corpus callosum, corona radiata, forceps major, and cerebral peduncles.


Input: This is different from numerous previous descriptions of the CT pattern in ALD.

ALD


Input: Type II ALD does not appear to have been seen in any other leukoencephalopathy and is probably specific for a phenotypic variant or an evolving stage of ALD..

Type II ALD

leukoencephalopathy

ALD


Input: Further evidence for heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Papua New Guinea.

glucose-6-phosphate dehydrogenase deficiency


Input: Four new G6PD variants have been characterized in individuals from Papua New Guinea.


Input: This study demonstrates that the previously reported Markham variant and the newly characterized Salata variant may be widely distributed in Papua New Guinea.


Input: Th data presented here together with those of previously published studies demonstrate a degree of heterogeneity of G6PD deficiency that is much higher than that in other regions of the world where G6PD deficiency is common..

G6PD deficiency

G6PD deficiency


Input: Increased incidence of cataracts in male subjects deficient in glucose-6-phosphate dehydrogenase.

cataracts

deficient in glucose-6-phosphate dehydrogenase


Input: Glucose-6-phosphate dehydrogenase (G6PD) deficiency in RBCs was found significantly more frequently in 210 male cataractous patients than in 672 control subjects of Sardinian origin.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

cataractous


Input: The frequency of the deficiency was increasingly higher in presenile cataracts.

cataracts


Input: In the G6PD-deficient group, the incidence of cortical and total cataracts was also increased.

cortical and total cataracts


Input: It is suggested that decrease of the G6PD activity in the lens, which accompanies its deficiency in the erythrocyte, might play a role in the cataracto-genesis of these patients.


Input: Moreover, G6PD deficiency should be added to other conditions, such as the galactosemic states and riboflavin deficiency, where cataracts represent a sensitive indicator of metabolic abnormalities of the RBC..

G6PD deficiency

galactosemic

riboflavin deficiency

cataracts

metabolic abnormalities


Input: Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood.

very-long-chain acyl-CoA dehydrogenase deficiency

cardiomyopathy

sudden death


Input: beta-Oxidation of long-chain fatty acids provides the major source of energy in the heart.


Input: Defects in enzymes of the beta-oxidation pathway cause sudden, unexplained death in childhood, acute hepatic encephalopathy or liver failure, skeletal myopathy, and cardiomyopathy.

sudden, unexplained death

hepatic encephalopathy

liver failure

skeletal myopathy

cardiomyopathy


Input: Very-long-chain acyl-CoA dehydrogenase [VLCAD; very-long-chain-acyl-CoA (acceptor) 2, 3-oxidoreductase, EC 1. 3 3. 99 99. 13] catalyzes the first step in beta-oxidation.


Input: We have isolated the human VLCAD cDNA and gene and determined the complete nucleotide sequences.


Input: Polymerase chain reaction amplification of VLCAD mRNA and genomic exons defined the molecular defects in two patients with VLCAD deficiency who presented with unexplained cardiac arrest and cardiomyopathy.

VLCAD deficiency

cardiac arrest

cardiomyopathy


Input: In one, a homozygous mutation in the consensus dinucleotide of the donor splice site (g + 1--> a) was associated with universal skipping of the prior exon (exon 11).


Input: The second patient was a compound heterozygote, with a missense mutation, C1837--> T, changing the arginine at residue 613 to tryptophan on one allele and a single base deletion at the intron-exon 6 boundary as the second mutation.


Input: This initial delineation of human mutations in VLCAD suggests that VLCAD deficiency reduces myocardial fatty acid beta-oxidation and energy production and is associated with cardiomyopathy and sudden death in childhood.

VLCAD deficiency

cardiomyopathy

sudden death


Input: Aberrant subcellular localization of BRCA1 in breast cancer.

breast cancer


Input: The BRCA1 gene product was identified as a 220-kilodalton nuclear phosphoprotein in normal cells, including breast ductal epithelial cells, and in 18 of 20 tumor cell lines derived from tissues other than breast and ovary.

tumor


Input: In 16 of 17 breast and ovarian cancer lines and 17 of 17 samples of cells obtained from malignant effusions, however, BRCA1 localized mainly in cytoplasm.

breast and ovarian cancer


Input: Absence of BRCA1 or aberrant subcellular location was also observed to a variable extent in histological sections of many breast cancer biopsies.

breast cancer


Input: These findings suggest that BRCA1 abnormalities may be involved in the pathogenesis of many breast cancers, sporadic as well as familial..

BRCA1 abnormalities

breast cancers


Input: Mapping of the mouse homologue of the Wilson disease gene to mouse chromosome 8.

Wilson disease


Input: ATP7B, the gene altered in Wilson disease (WD) patients, lies in a block of homology shared between human chromosome 13q14 and the central region of mouse chromosome 14.

Wilson disease

WD


Input: However, we have mapped the murine homologue of ATP7B (Atp7b) to mouse chromosome 8 by somatic cell hybrid analysis.


Input: Analysis of 80 interspecific backcross offspring was used to position Atp7b close to D8Mit3 and another ATPase locus, Atp4b, on mouse chromosome 8.


Input: ATP4B lies in 13q34 and is separated from ATP7B by several loci whose mouse homologues map to mouse chromosome 14.


Input: The assignment of Atp7b to mouse chromosome 8 identifies a previously unrecognized region of homology between this chromosome and human chromosome 13.


Input: This assignment suggests a possible location for the toxic milk mutation in the mouse, which has been proposed as a homologue of WD..

WD


Input: Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

breast and ovarian cancer


Input: Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer.

breast cancer


Input: We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1.

breast and/or ovarian cancer


Input: Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported.


Input: We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family.

breast to ovarian cancer


Input: Our data suggest a transition in risk such that mutations in the 3 third of the gene are associated with a lower proportion of ovarian cancer.

ovarian cancer


Input: Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently..


Input: Hereditary deficiency of the seventh component of complement and recurrent meningococcal infection: investigations of an Irish family using a novel haemolytic screening assay for complement activity and C7 M/N allotyping.

deficiency of the seventh component of complement

meningococcal infection


Input: Terminal complement component deficiency predisposes to meningococcal infection and is inherited in an autosomal co-dominant manner.

Terminal complement component deficiency

meningococcal infection


Input: An Irish family is described, in which 2 of 3 brothers had recurrent meningococcal infection.

meningococcal infection


Input: A novel screening assay was used to investigate for terminal complement deficiency and the 2 affected brothers were found to be completely deficient in the seventh component of complement (C7).

terminal complement deficiency

completely deficient in the seventh component of complement


Input: Enzyme-linked immunosorbent assay for C7 revealed lower than normal levels in the remaining brother and parents.


Input: C7 M/N protein polymorphism allotyping, used to investigate the segregation of the C7 deficiency genes, showed that the apparently complement sufficient brother was heterozygous C7 deficient and a carrier of one of the deficiency genes.

C7 deficiency

C7 deficient


Input: Complement screening should be carried out in any individual suffering recurrent meningococcal infection or infection with an uncommon meningococcal serogroup.

meningococcal infection

meningococcal


Input: Identification of complement deficient patients allows the implementation of strategies to prevent recurrent infection..

complement deficient


Input: Molecular basis of subtotal complement C6 deficiency.

subtotal complement C6 deficiency


Input: A carboxy-terminally truncated but functionally active C6.


Input: Individuals with subtotal complement C6 deficiency possess a C6 molecule that is 14% shorter than normal C6 and present in low but detectable concentrations (1-2% of the normal mean).

subtotal complement C6 deficiency


Input: We now show that this dysmorphic C6 is bactericidally active and lacks an epitope that was mapped to the most carboxy-terminal part of C6 using C6 cDNA fragments expressed as fusion proteins in the pUEX expression system.


Input: We thus predicted that the abnormal C6 molecule might be carboxy-terminally truncated and sought a mutation in an area approximately 14% from the carboxy-terminal end of the coding sequence.


Input: By sequencing PCR-amplified products from this region, we found, in three individuals from two families, a mutation that might plausibly be responsible for the defect.


Input: All three have an abnormal 5 splice donor site of intron 15, which would probably prevent splicing.


Input: An in-frame stop codon is found 17 codons downstream from the intron boundary, which would lead to a truncated polypeptide 13.


Input: 5% smaller than normal C6.


Input: This result was unexpected, as earlier studies mapped the C5b binding site, or a putative enzymatic region, to this part of C6.


Input: Interestingly, all three subjects were probably heterozygous for both subtotal C6 and complete C6 deficiency.

subtotal C6 and complete C6 deficiency


Input: Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation.

Myotonic dystrophy


Input: The trinucleotide expansion mutation causing myotonic dystrophy is in the 3 untranslated region of a protein kinase gene.

myotonic dystrophy


Input: The molecular mechanisms by which the expanded repeat causes the clinically variable and multisystemic disease, myotonic dystrophy, are not understood.

multisystemic disease

myotonic dystrophy


Input: It has been particularly difficult to rationalize the dominant inheritance with the fact that the expansion mutation lies outside of the protein-encoding gene elements, and should not be translated into protein.


Input: Here we use muscle biopsies from classical adult-onset myotonic dystrophy patients to study the accumulation of transcripts from both the normal and expanded DM kinase genes in patient muscle, and compare the results to normal and myopathic controls.

myotonic dystrophy

DM

myopathic


Input: We found relatively small decreases of DM kinase RNA in the total RNA pool from muscle; however, these reductions were not disease specific.

DM


Input: Analysis of poly (A) + RNA showed dramatic decreases of both the mutant and normal DM kinase RNAs, and these changes were disease-specific.

DM


Input: Our findings are consistent with a novel molecular pathogenetic mechanism for myotonic dystrophy both the normal and expanded DM kinase genes are transcribed in patient muscle, but the abnormal expansion-containing RNA has a dominant effect on RNA metabolism by preventing the accumulation of poly (A) + RNA.

myotonic dystrophy

DM


Input: The ability of the expansion mutation to alter accumulation of poly (A) + RNA in trans suggests that myotonic dystrophy may be the first example of a dominant-negative mutation manifested at the RNA level..

myotonic dystrophy


Input: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

breast and ovarian cancer


Input: A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods.

breast and ovarian cancer


Input: Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles.


Input: The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation.


Input: The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids.


Input: This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins.


Input: Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology..

breast and ovarian cancer

breast cancer


Input: Molecular characterization of galactosemia (type 1) mutations in Japanese.

galactosemia


Input: We characterized two novel mutations of the galactose-1-phosphate uridyltransferase (GALT) gene in two Japanese patients with GALT deficiency and identified N314D and R333W mutations, previously found in Caucasians.

GALT deficiency


Input: One novel missense mutation was an G-to-A transition in exon 8, resulting in the substitution of arginine by histidine at the codon 231 (R231H).


Input: GALT activity of the R231H mutant construct was reduced to 15% of normal controls in a COS cell expression system.


Input: The other was a splicing mutation, an A-to-G transition at the 38th nucleotide in exon 3 (318A--> G), resulting in a 38-bp deletion in the GALT cDNA by activating a cryptic splice acceptor site.


Input: In seven Japanese families (14 alleles for classic form and one allele for Duarte variant) with GALT deficiency, the R231H and 318A--> G mutations were found only on both alleles of the proband.

GALT deficiency


Input: The N314D and R333W mutations were found on one allele each.


Input: The Q188R was prevalent in the United States but not in Japanese patients.


Input: The N314D mutation was associated with the Duarte variant in Japanese persons, as well as in the United States.


Input: We speculate that classic galactosemia mutations appear to differ between Japanese and Caucasian patients.

classic galactosemia


Input: Our limited data set on galactosemia mutations in Japanese suggests that the N314D GALT mutation encoding the Duarte variant arose before Asian and Caucasian people diverged and that classic galactosemia mutations arose and/or accumulated after the divergence of Asian and Caucasian populations..

galactosemia

classic galactosemia


Input: Three novel aniridia mutations in the human PAX6 gene.

aniridia


Input: Aniridia (iris hypoplasia) is an autosomal dominant congenital disorder of the eye.

Aniridia

iris hypoplasia

autosomal dominant congenital disorder of the eye


Input: Mutations in the human aniridia (PAX6) gene have now been identified in many patients from various ethnic groups.

aniridia


Input: In the study reported here we describe PAX6 mutations in one sporadic and five familial cases with aniridia.

aniridia


Input: Of the four different mutations identified, one was identical to a previously reported mutation (C--> T transition at codon 240), and three were novel two in the glycine-rich region and one in the proline/serine/threonine-rich (PST) region.


Input: One PAX6 mutation found in the PST region was associated with cataracts in an aniridia family.

cataracts

aniridia


Input: Another splice mutation in the PST domain occurred in an aniridia patient with anosmia (inability to smell).

aniridia

anosmia


Input: The six new aniridia cases reported here have mutations predicted to generate incomplete PAX6 proteins.

aniridia


Input: These results support the theory that human aniridia is caused by haploinsufficiency of PAX6..

aniridia

haploinsufficiency of PAX6


Input: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.


Input: Since BRCA1, the first major gene responsible for inherited breast cancer, was cloned, more than 50 unique mutations have been detected in the germline of individuals with breast and ovarian cancer.

inherited breast cancer

breast and ovarian cancer


Input: In high-risk pedigrees, female carriers of BRCA1 mutations have an 80-90% lifetime risk of breast cancer, and a 40-50% risk of ovarian cancer.

breast cancer

ovarian cancer


Input: However, the mutation stats of individuals unselected for breast or ovarian cancer has not been determined, and it is not known whether mutations in such individuals confer the same risk of cancer as in individuals from the high-risk families studied so far.

breast or ovarian cancer

cancer


Input: Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, we have determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference individuals not selected for ethnic origin.

cancer


Input: We observed the 185delAG mutation in 0.


Input: 9% of Ashkenazim (95% confidence limit, 0. 4-1. 8%) and in none of the reference samples.


Input: Our results suggest that one in a hundred women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.

breast and/or ovarian cancer


Input: Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies.


Input: The Huntington disease (HD) phenotype is associated with expansion of a trinucleotide repeat in the IT15 gene, which is predicted to encode a 348-kDa protein named huntington.

Huntington disease

HD


Input: We used polyclonal and monoclonal anti-fusion protein antibodies to identify native huntingtin in rat, monkey, and human.


Input: Western blots revealed a protein with the expected molecular weight which is present in the soluble fraction of rat and monkey brain tissues and lymphoblastoid cells from control cases.


Input: In lymphoblastoid cell lines from juvenile-onset heterozygote HD cases, both normal and mutant huntingtin are expressed, and increasing repeat expansion leads to lower levels of the mutant protein.

HD


Input: Immunocytochemistry indicates that huntingtin is located in neurons throughout the brain, with the highest levels evident in larger neurons.


Input: In the human striatum, huntingtin is enriched in a patch-like distribution, potentially corresponding to the first areas affected in HD.

HD


Input: Subcellular localization of huntingtin is consistent with a cytosolic protein primarily found in somatodendritic regions.


Input: Huntingtin appears to particularly associate with microtubules, although some is also associated with synaptic vesicles.


Input: On the basis of the localization of huntingtin in association with microtubules, we speculate that the mutation impairs the cytoskeletal anchoring or transport of mitochondria, vesicles, or other organelles or molecules..


Input: Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus.

spinocerebellar ataxia 3/Machado-Joseph disease


Input: The spinocerebellar ataxia 3 locus (SCA3) for type I autosomal dominant cerebellar ataxia (ADCA type I), a clinically and genetically heterogeneous group of neurodegenerative disorders, has been mapped to chromosome 14q32.

spinocerebellar ataxia 3

type I autosomal dominant cerebellar ataxia

ADCA type I

neurodegenerative disorders


Input: 1 1.


Input: ADCA type I patients from families segregating SCA3 share clinical features in common with those with Machado-Joseph disease (MJD), the gene of which maps to the same region.

ADCA type I

Machado-Joseph disease

MJD


Input: We show here that the disease gene segregating in each of three French ADCA type I kindreds and in a French family with neuropathological findings suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy carries an expanded CAG repeat sequence located at the same locus as that for MJD.

ADCA type I

dentatorubropallidoluysian atrophy

MJD


Input: Analysis of the mutation in these families shows a strong negative correlation between size of the expanded CAG repeat and age at onset of clinical disease.


Input: Instability of the expanded triplet repeat was not found to be affected by sex of the parent transmitting the mutation.


Input: Evidence was found for somatic and gonadal mosaicism for alleles carrying expanded trinucleotide repeats.


Input: Overexpression of DM20 messenger RNA in two brothers with Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease


Input: Pelizaeus-Merzbacher disease is a rare, sex-linked recessive, dysmyelinating disease of the central nervous system that has been associated with mutations in the myelin proteolipid protein (PLP) gene.

Pelizaeus-Merzbacher disease

rare, sex-linked recessive, dysmyelinating disease of the central nervous system


Input: Only 25% of patients studied with Pelizaeus-Merzbacher disease have exonic mutations in this gene, the underlying cause of the disease in the remaining patients is unknown.

Pelizaeus-Merzbacher disease


Input: The PLP gene encodes two major alternatively spliced transcripts called PLP and DM20.


Input: PLP messenger RNA is specifically expressed in central nervous system tissue, whereas DM20 messenger RNA is found in central nervous system, cardiac, and other tissues.


Input: We studied cultured skin fibroblasts from 2 brothers with Pelizaeus-Merzbacher disease who exhibited no detectable exonic mutation of the PLP gene.

Pelizaeus-Merzbacher disease


Input: Examination of RNA from these cells showed that the level of DM20 messenger RNA is elevated sixfold relative to male control skin fibroblasts.


Input: An unrelated female carrier, also with no detectable exonic mutation, showed a threefold increase in DM20 messenger RNA in cultured skin fibroblasts.


Input: Our findings suggest that in some patients, Pelizaeus-Merzbacher disease is caused by overexpression of PLP gene transcripts, and that in these families a 50% increase of DM20 messenger RNA in females, relative to the increase in affected males, can identify a female carrier..

Pelizaeus-Merzbacher disease


Input: The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene.

Wiskott-Aldrich syndrome

X-linked congenital thrombocytopenia


Input: The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency.

Wiskott-Aldrich syndrome

WAS

X-linked recessive disorder

thrombocytopenia

eczema

immunodeficiency


Input: Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency.

WAS

congenital X-linked thrombocytopenia

XLT

eczema

immune deficiency


Input: Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations.

WAS

WAS

WAS


Input: Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms.

WAS


Input: Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects.

WAS


Input: Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9.

XLT


Input: Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination.

WAS


Input: These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations..

XLT

WAS


Input: Myotonia levior is a chloride channel disorder.

Myotonia levior

chloride channel disorder


Input: The group of dominant non-dystrophic myotonias, comprising disorders characterized by clinically similar forms of myogenic muscle stiffness, is genetically inhomogeneous.

dominant non-dystrophic myotonias


Input: Dominant myotonia congenita (Thomsens disease) is linked to CLCN1, the gene encoding the major muscle chloride channel, localized on chromosome 7q35.

Dominant myotonia congenita

Thomsens disease


Input: In contrast, dominant myotonias sensitive to potassium are caused by point mutations in SCN4A on chromosome 17q, the gene for the alpha subunit of the adult skeletal muscle sodium channel.

dominant myotonias


Input: No linkage or molecular genetic data are as yet available on myotonia levior characterized by milder symptoms and later onset of myotonia than in Thomsens disease, and absence of muscle hypertrophy.

myotonia levior

myotonia

Thomsens disease

muscle hypertrophy


Input: We report a CLCN1 Gln-552-Arg substitution for a family with dominant inheritance previously diagnosed to have myotonia levior.

myotonia levior


Input: Thus, this disorder appears as a variant of Thomsens disease due to mutations leading to low clinical expressivity.

Thomsens disease


Input: In addition, we report a novel Ile-290-Met CLCN1 mutation for a typical Thomsen pedigree.


Input: In another family previously diagnosed as having Thomsens disease, we unexpectedly found a CLCN1 14 bp deletion known to cause recessive myotonia, and a rare Trp-118-Gly polymorphism..

Thomsens disease

recessive myotonia


Input: Southern analysis reveals a large deletion at the hypoxanthine phosphoribosyltransferase locus in a patient with Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome


Input: Whole genomic hprt clones were used in Southern analysis to screen the integrity of the hprt gene in a family that includes a patient with HPRT enzyme deficiency causal to Lesch-Nyhan syndrome.

HPRT enzyme deficiency

Lesch-Nyhan syndrome


Input: A 5 kb DNA sequence deletion was found to have its endpoints in the first and third introns.


Input: The probes identified the carrier status of female family members, aided by an RFLP carried by the mothers normal X-chromosome..


Input: Characterisation of molecular defects in X-linked amelogenesis imperfecta (AIH1).

X-linked amelogenesis imperfecta


Input: Amelogenins are an heterogenous family of proteins produced by ameloblasts of the enamel organ during tooth development.


Input: Disturbances of enamel formation occur in amelogenesis imperfecta, a clinically heterogenous group of inherited disorders characterised by defective enamel biomineralisation.

amelogenesis imperfecta

inherited disorders


Input: An amelogenin gene, AMGX, has been mapped to the short of the X chromosome (Xp22. 1-p22. 3) and has been implicated in the molecular pathology of X-linked amelogenesis imperfecta (AIH1).

X-linked amelogenesis imperfecta


Input: We have identified three families exhibiting AIH1 and screened the AMGX gene for mutations using single-strand conformational polymorphism analysis and DNA sequencing.


Input: Three novel mutations were identified a C-T substitution in exon 5, and a G-T substitution and single cytosine deletion in exon 6, confirming the existence of extensive allelic heterogeneity in this condition.


Input: The identification of family-specific mutations will enable early identification of affected individuals and correlation of clinical phenotype with genotype will facilitate an objective system of disease classification.


Input: Frequency of exon 15 missense mutation (442D: G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects.

hyperalphalipoproteinemic


Input: Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester from high density lipoprotein (HDL) to apo B-containing lipoproteins.


Input: The hyperalphalipoproteinemia caused by CETP deficiency is fairly common in Japan and one of the most common mutations in the CETP gene is the splicing defect of the intron 14, the allelic frequency of which has been shown to be 0.

hyperalphalipoproteinemia

CETP deficiency


Input: 0049 in the Japanese general population.


Input: Recently, we have reported a missense mutation in exon 15 of the CETP gene (442D G), showing a dominant effect on the CETP activity and HDL-cholesterol level.


Input: In the current study, we determined the frequency of this new mutation in Japanese hyperalphalipoproteinemic (HDL-cholesterol > or = 100 mg/dl) subjects.

hyperalphalipoproteinemic


Input: A rapid and easy screening method for this new mutation was developed using a polymerase chain reaction (PCR)-mediated site-directed mutagenesis.


Input: Among 117 Japanese hyperalphalipoproteinemic subjects (HDL-cholesterol; 116. 7 +/-16. 5 mg/dl, mean +/-S. D.) without the intron 14 splice defect, three homozygotes (2. 5%) and 34 heterozygotes (29. 1%) were found to have the 442D G mutation.

hyperalphalipoproteinemic


Input: The relative allelic frequency of this mutation was calculated to be 0.


Input: One of the homozygotes for the 442D G mutation was the patient previously described by us as having hyperalphalipoproteinemia with corneal opacity and coronary heart disease.

hyperalphalipoproteinemia

corneal opacity

coronary heart disease


Input: This was the first reported subject homozygous for the CETP deficiency who also demonstrated atherosclerotic symptoms.

CETP deficiency

atherosclerotic symptoms


Input: In homozygous subjects, CETP activity ranged from 37% to 62% of the normal value, which was consistent with the results obtained from the transient expression experiment previously reported; however, the specific activity of CETP was not as low as expected.


Input: (ABSTRACT TRUNCATED AT 250 WORDS)


Input: Mucopolysaccharidosis type IVA: common double deletion in the N-acetylgalactosamine-6-sulfatase gene (GALNS).

Mucopolysaccharidosis type IVA


Input: Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine-6-sulfatase (GALNS).

Mucopolysaccharidosis IVA

MPS IVA

autosomal recessive disorder

deficiency in N-acetylgalactosamine-6-sulfatase


Input: We found two separate deletions of nearly 8.


Input: 0 and 6.


Input: 0 kb in the GALNS gene, including some exons.


Input: There are Alu repetitive elements near the breakpoints of the 8.


Input: 0-kb deletion, and this deletion resulted from an Alu-Alu recombination.


Input: The other 6.


Input: 0-kb deletion involved illegitimate recombinational events between incomplete short direct repeats of 8 bp at deletion breakpoints.


Input: The same rearrangement has been observed in a heteroallelic state in four unrelated patients.


Input: This is the first documentation of a common double deletion a gene that is not a member of a gene cluster.


Input: Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer.

breast/ovarian cancer

male breast cancer