摘要:

AbstractHemophilia is a common X‐linked coagulation disorder due to deficiency of factor VIII. The factor VIII gene has been cloned in 1984 and a large number of mutations that cause hemophilia A have been identified in the last decade. The most common of the mutations is an inversion of factor VIII that accounts for nearly 45% of patients vvith severe hemophilia A. This review lists all the factor VIII mutations identified to date and briefly discusses their functional significance. © 1995 Wiley‐Liss,

ISSN:1059-7794    

DOI:10.1002/humu.1380050102

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

年代:1995

数据来源: WILEY

摘要:

AbstractThree intragenic microsatellites of the CFTR gene, a TA and a CA repeats, namely IVSl7bTA and IVSl7bCA, located in intron 17b and a CA repcat (IVS8CA) located in intron 8 of the CFTR gene, were analyzed in a large sample of Italian cystic fibrosis (CF) and normal chromosomes. Linkage disequilibrium was evaluated between each marker and different CF mutations on a total of 377 CF and 358 normal chromosomes. Our results are consistent with the hypothesis that all AF508 chromosomes derive from a single mutational event. The same hypothesis is valid for mutations G542X, N1303K, 1717‐1IG→, which might have been originated more recently than δF508. © 1995 Wiley‐ Li

ISSN:1059-7794    

DOI:10.1002/humu.1380050103

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

年代:1995

数据来源: WILEY

摘要:

AbstractA large Manitoba Hutterite kindred with X‐linked receptor negative complete androgen insensitivity syndrome (CAIS) was studied. In attempts to identify all carriers of the syndrome in this kindred, using the androgen receptor (AR) cDNA, we have found a novel diagnostic Mspl polymorphic pattern, which cosegregates with the disease. This polymorphism was not detected in 79 unrelated X‐chromosomes of which 22 were from Hutterite controls. We were able to localize the polymorphism to exon 4, which is known to encode part of the androgen receptor hormone binding domain. A single base substitution (T→C) was detected, which creates a new Mspl site. This novel transition mutation replaces Leu‐676 with Pro at a site which is conserved in numerous members of the steroid receptor gene family. Sequencing all 8 exons of the AR revealed the Leu‐676→Pro mutation as the only change in the primary structure of the receptor. Transfection of COS‐l cells with an expression vector of the mutant AR demonstrates that this point mutation of nucleotide 2558 abolishes receptor binding activity. The mutation can easily be detected by MspI digestion of the polymerase chain reaction (PCR) amplified exon 4 product.© 1995 w

ISSN:1059-7794    

DOI:10.1002/humu.1380050104

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe molecular basis of mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency was studied in two patients (GK11 and GK16). Fibroblasts from each patient had detectable immunoreactive T2 polypeptide (CRM). In pulse‐chase experiments, fibroblasts from GK11 had two types of CRM: one (type I CRM) disappeared after a 24‐hr chase and migrated more slowly than that of the normal control; the other (type II CRM) was detected with a small amount even after a 72‐hr chase and had normalelectrophoretic mobility. GK16's fibroblasts had a CRM (type III) which was also detectable even after a 72‐hr chase and showed a slower mobility than type I CRM. By analyzing amplified cDNA and genomic fragments, we showed that both patients are genetic compounds; GK11 for the mutations N158D and T297M, and GK16 for the mutations A301P and IVS8 ( + 1). Expression analyses confirmed that mutant T2 subunits with N158D, T297M, and A301P correspond to type I, II, and III CRM, respectively. Among them, only the mutant T2 polypeptide with T297M appeared to have a detectable residual activity, in spite of its instability. Cotransfection of two cDNAs containing N158D and T297M suggested that heterotetramer formation reduces residual activity in GK11 cells.© 1995 wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380050105

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

年代:1995

数据来源: WILEY

摘要:

AbstractSix new mutations have been identified in the CFTR gene. These mutations, representing three different categories—missense (R31L, W1098R), nonsense (E1104X), and frameshift (441delA, 681delC, 1461ins4)—are located in exons 2, 4, 5, 9, and 17b of the gene and presumed to cause cystic fibrosis (CF) in patients. All these mutations are probably rare in the population, as no additional examples were found for any of them in a cohort of 545 CF patients. Our study also revealed a benign sequence variation (3499 + 45T→C) in intron 17b. © 1995 Wiley‐L

ISSN:1059-7794    

DOI:10.1002/humu.1380050106

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe spectrum of somatic TP53 single basepair substitutions detected in 955 cancers was compared with that of 2,224 different germline mutations in 279 different human genes (other than TP53), reported as the cause of inherited disease. This comparison reveals that, disregarding a relatively small subset (12%) of TP53 mutations that probably result from the action of exogenous mutagens, both the relative rates and the nearest‐neighbor spectra of single basepair substitutions are similar in the two datasets. This spectral resemblance suggests that a substantial proportion of cancer‐associated somatic TP53 mutations result from endogenous cellular mechanisms. The likelihood of clinical observation of a particular mutation type differs, however, between tumors and genetic diseases, when the chemical properties of the resulting amino acid substitutions are considered. Together with a sixfold higher observation likelihood for mutations at evolutionary conserved residues, this finding argues that selection is a critical factor in determining which TP53 mutations are found to be associated with human cancer. © 1995 Wiley‐Lis

ISSN:1059-7794    

DOI:10.1002/humu.1380050107

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe genetic polymorphism of human apolipoprotein A‐IV was investigated in Hungarian blood donors (n = 202) by isoelectric focusing (IEF) of pfasma samples followed by immunoblotting. The frequency of apo A‐IV alleles was f(A‐IV1) = 0.95, f(A‐IV2) = 0.039 and f(A‐IV3) = 0.002. This frequency distribution is significantly different from other Caucasian populations (P<0.05). The association of apo A‐IV phenotypes with HDL‐cholesterol concentration which was previously described for two other European populations was only of borderline significance (P = 0.08).Three previously undescribed apo A‐IV variants, designated Budapest‐1, Budapest‐2 and Budapest‐3, were detected by IEF. The mutant proteins are not associated with alterations in the lipid/ lipoprotein concentrations in heterozygotes. DN A‐sequencing reveafed two point mutations (Arg285→ Cys and Thr347→ Ser) in exon 3 of apo A‐IV‐Budapest‐1 and a Glu → Lys substitution at position 24 in exon 2 of apo A

ISSN:1059-7794    

DOI:10.1002/humu.1380050108

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

年代:1995

数据来源: WILEY

摘要:

AbstractVon Hippel‐Lindau disease (VHL) is an inherited neoplastic disease characterized by a predisposition to develop retinal angiomas, central nervous system hemangioblastomas, renal cell carcinomas, pancreatie cysts, and pheochromocytomas. The VHL gene was recently isolated by positional cloning. The cDNA encodes 852 nucleotides in 3 exons. The VHL gene is unrelated to any known gene families. We identified germline mutations in 85/114 (75%) of VHL families. Clinical heterogeneity is a well‐known feature of VHL. VHL families were classified into 2 types based on the presence or absence of pheochromocytoma. The types of mutations responsible for VHL without pheochromocytoma (VHL type 1) differed from those responsible for VHL with pheochromocytoma (VHL type 2). Fifty‐six % of the mutations responsible for VHL type l were microdeletions/insertions, nonsense mutations, or deletions; 96% of the mutations responsible for VHL type 2 were missense mutations. Specific mutations in codon 238 accounted for 43% of the mutations responsible for VHL type 2. The mutations identified in these families will be useful in presymptomatic diagnosis. The identification of mutations associated with phenotypes contributes to the understanding of fundamental genetic mechanisms of VHL disease. © 1995 Wiley‐L

ISSN:1059-7794    

DOI:10.1002/humu.1380050109

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

年代:1995

数据来源: WILEY

摘要:

AbstractWe identified a de novo mutation in the peripheral myelin protein (PMP22) gene of a patient with Déjérine‐Sottas neuropathy. Single‐stranded conformation analysis of PCR‐amplified DNA fragments showed an additional fragment for exon 1 in the patient, which was absent in the unaffected parents. Sequence analysis showed a de novo point mutation C85→A that results in an amino acid substitution Hisl2Gln in the first transmembrane domain of PMP22. This provides further evidence that sporadic cases of Déjérine‐Sottas neuropathy can be due to dominant single base substitutions.© 1995 w

ISSN:1059-7794    

DOI:10.1002/humu.1380050110

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

年代:1995

数据来源: WILEY

摘要:

AbstractWe have developed a rapid screening method to detect a recurrent mutation in the neurofibromatosis type l gene. Using gene amplification and hybridization with allele‐specific oligonucleotides, we screened 97 unrelated affected individuals for the recurrent C→T substitution in codon 1947. The mutation was detected in l patient and found to cosegregate with the disease phenotype in the patient's family. Although the estimated prevalence of this mutation is low, rapid screening of different patient cohorts would identify multiple individuals carrying the same mutation. Such data would provide the first opportunity for examining correlations between phenotypic characteristics and molecular genotype and would allow clinicians to offer early diagnosis and prenatal screening to affected families. A format for the comparison of phenotypic features in other settings is presented. © 1995 Wiley‐Lis

ISSN:1059-7794    

DOI:10.1002/humu.1380050111

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

年代:1995

数据来源: WILEY