摘要:

AbstractMutations in the muscle phosphofructokinase gene (PFK‐M) result in a metabolic myopathy characterized by exercise intolerance and compensated hemolysis. PFK deficiency, glycogenosis type VII (Tarui disease) is a rare, autosomal, recessively inherited disorder. Multiple mutations, including splicing defects, frameshifts, and missense mutations, have recently been identified in patients from six different ethnic backgrounds establishing genetic heterogeneity of the disease. There is no obvious correlation between the genotype and phenotypic expression of the disease. PFK‐M deficiency appears to be prevalent among people of Ashkenazi Jewish descent. Molecular diagnosis is now feasible for Ashkenazi patients who share two common mutations in the gene; the more frequent is an exon 5 splicing defect, which accounts for ∼68% of mutant alleles in this population. © 1995 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of

ISSN:1059-7794    

DOI:10.1002/humu.1380060102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

ISSN:1059-7794    

DOI:10.1002/humu.1380060103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThyroid peroxidase (TPO) is the key enzyme in the synthesis of thyroid hormones. Defects in the TPOgene are reported to be the cause of congenital hypothyroidism due to a Total Iodide Organification Defect (TIOD). This type of defect, where iodide taken up by the thyroid gland cannot be oxidized and bound to protein, is the most common hereditary inborn error causing congenital hypothyroidism in the Netherlands. Denaturing Gradient Gel Electrophoresis (DGGE) of PCR amplified genomic DNA was used to screen for mutation in the TPO gene of TIOD patients from nine apparently unrelated families, and seven different mutations were detected. Three frameshift mutations were found: a 20 bp duplication in exon 2, a 4 bp duplication in exon 8, and an insertion of a single nucleotide (C) at pos. 2505 in exon 14. In addition, four single nucleotide substitutions were identified: one single‐base, mutation resulted in a premature termination codon (C → T at pos. 1708 in exon 10), two single‐base substitutions changed an amino acid in highly conserved regions of the gene (Tyr → Asp in exon 9 and Glu → Lys in exon 14). The fourth single‐base mutation located at the exon 10/intron 10 border altered a conserved Gly into Ser and could also affect splicing. Nine TIOD patients from five families were compound heterozygotes and six patients from four families were homozygous for one of the mentioned mutations in the TPO gene. © 1995 Wil

ISSN:1059-7794    

DOI:10.1002/humu.1380060104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractMutations in the insulin receptor gene can cause genetic syndromes associated with extreme insulin resistance. We have investigated a patient with leprechaunism (leprechaun/Qatar‐1) born of a consanguineous marriage. Postnatally, the proband had episodes of severe hypoglycemia and hyperinsulinernia, with blood glucose levels ranging from 0.9 to 9.9 mmol/L. The C peptide concentration with 1880 nmol/L, and the total insulin concentration was 1409 mU/L. The patient died outside the hospital at the age of four months. All 22 exons of the patient's insulin reseptor gene were screened for mutations using denaturing gradient gel electrophoresis. Thereafter, the nucleotide sequences of selected exons were determined directly. The patient was homozygous for a mutation in exon 13; thirteen base pairs were deleted and replaced by a 5 b.p. sequence. This mutation shifts the reading frame and introduces a premature chain termination codon downstream in exon 13. Thus, the mutantallele is predicted to be a null allele that encodes a truncated receptor lacking both transmembrane and tyrosine kinase domains. © 1995 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of Ame

ISSN:1059-7794    

DOI:10.1002/humu.1380060105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractIn order to establish counseling guidelines and aid carrier risk assessment, we sought to establish the frequencies of cystic fibrosis (CF) mutations that are present in CF families living in the Ile de France region, a region notable for its ethnic heterogeneity. We studied 470 CF chromosomes in which we identified more than 90% of the CF mutations. We systematically screened 21 exons and the adjacent sequences of the CF transmembrane conductance regulator (CFTR) gene by denaturing gradient gel electrophoresis using chemical clamps. We detected 41 different CF mutations located in 14 exons. One of these mutations had not been previously described. Given the heterogeneity of these mutations, population screening does not appear to be readily feasible in our population. © 1995 Wiley‐Liss, I

ISSN:1059-7794    

DOI:10.1002/humu.1380060106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractA new approach for the detection of β‐thalassemia mutations has been applied, based on competitive oligonucleotide priming (COP) of in vitro DNA amplification at the mutation site. This method allows genotyping of the template DNA, through differential labeling of the allele‐specific competitive oligoprimers and biotinylation of the common reverse primer. The system provides a basis for rapid, simple, and reliable detection of the numerous known β‐thalassemia mutations, revealing the precise nature of the mismatch in each case, and thereby facilitating the molecular genetic analysis of the disease. © 1995 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380060107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractWe characterized two novel mutations of the galactose‐1‐phosphate uridyltransferase (GALT) gene intwo Japanese patients with GALT deficiency and identified N314D and R333W mutations, previouslyfound in Caucasians. One novel missense mutation was an G‐to‐A transition in exon 8, resulting in thesubstitution of arginine by histidine at the codon 231 (R231H). GALT activity of the R231H mutantconstruct was reduced to 15% of normal controls in a COS cell expression system. The other was asplicing mutation, an A‐to‐G transition at the 38th nucleotide in exon 3 (318A→G), resulting in a38‐bp deletion in the GALT cDNA by activating a cryptic splice acceptor site. In seven Japanesefamilies (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. The N314D and R333W mutations were found on one allele each. The Q188R was prevalent in the United States butnot in Japanese patients. The N314D mutation was associated with the Duarte variant in Japanesepersons, as well as in the United States. We speculate that classic galactosemia mutations appear todiffer between Japanese and Caucasian patients. Our limited data set on galactosemia mutations in Japanese suggests that the N314D GALT mutation encoding the Duarte variant arose before Asianand Caucasian people diverged and that classic galactosemia mutations arose and/or accumulated afterthe divergence of Asian and Caucasian populations. © 19

ISSN:1059-7794    

DOI:10.1002/humu.1380060108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractAniridia (iris hypoplasia) is an autosomal dominant congenital disorder of the eye. Mutations in the human aniridia (PAX6) gene have now been identified in many patients from various ethnic groups. In the study reported here we describe PAX6 mutations in one sporadic and five familial cases with aniridia. 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. One PAX6 mutation found in the PST region was associated with cataracts in an aniridia family. Another splice mutation in the PST domain occured in an aniridia patient with anosmia (inability to smell) The sixnew aniridia cases reported here have mutations predicted to generate incomplete PAX6 proteins. These results support the theory that human aniridia is caused by haploinsufficiency of PAX6. © 1995 Wiley‐L

ISSN:1059-7794    

DOI:10.1002/humu.1380060109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractCharcot‐Marie‐Tooth type 1 (CMT1) disease is an autosomal dominant neuropathy of the peripheral nerve. The majority of CMT 1 cases are due to a duplication of an 1.5‐Mb DNA fragment on chromosome 17pl1.2 (CMT la). Micromutations were found in the gene for peripheral myelin protein 22 (PMp22) located in the duplicated region of CMT la, and in the peripheral myelin protein zero (PO) located on chromosome lq21‐23 (CMT Ib). We have characterized two new mutations in the PO gene in two french families presenting CMT disease. Both mutations occur in the extracellular domain of the PO protein. One mutation is a de novo mutation and is from paternal origin. © 1995 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380060110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe α‐L‐iduronidase deficiency diseases (Mucopolysaccharidosis I) cover a spectrum of clinical severity ranging from the very severe (Hurler syndrome, MPS IH) through an intermediate (Hurler/Scheie syndrome, MPS IH/S) to a relatively mild form (Scheie syndrome, MPS IS). Numerous mutations of the gene encoding α‐L‐iduronidase (IDUA) are known in Hurler syndrome, but only three in the other disorders. We report on novel mutations of the IDUA gene in one patient with the Scheie syndrome and in three patients with the Hurler/Scheie syndrome. The novel mutations, all single base changes, encoded the substitutions R492P (Scheie), and X654G, P496L, and L490P (Hurler/Scheie). The L490P mutation was apparently homozygous, whereas each of the others was found in compound hettrozygosity with a Hurler mutation. The deleterious nature of the mutations was confirmed by absence of enzyme activity upon transfection of the corresponding mutagenized cDNAs into Cos‐1 cells. These results provide additional information for genotype—phenotype correlations. © 1995 W

ISSN:1059-7794    

DOI:10.1002/humu.1380060111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY