摘要:

AbstractThe low density lipoprotein (LDL) receptor is a cell surface transmembrane protein that mediates the uptake and lysosomal degradation of plasma LDL, thereby providing cholesterol to cells. Mutations disrupting the function of this receptor produce autosomal dominant familial hypercholesterolemia (FH). Affected individuals have elevated plasma levels of LDL, which causes premature coronary atherosclerosis. To date, 71 mutations in the LDL receptor gene have been characterized at a molecular level. In this report, we describe 79 additional mutations and review the insights that all 150 mutations have provided into the structure/function relationship of the receptor protein and the clinical manifestations of FH. © 1992 Wiley‐Liss, I

ISSN:1059-7794    

DOI:10.1002/humu.1380010602

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

年代:1992

数据来源: WILEY

摘要:

AbstractWe report here the result of a screening for germ‐line mutations in the adenomatous polyposis coli (APC) gene in 61 new familial adenomatous polyposis (FAP) patients as well as a summary of the results of 150 patients. Examination of the entire coding region of the APC gene, based on a ribonuclease protection assay coupled with the polymerase chain reaction (PCR), disclosed mutations that were considered to cause significant defects in the APC product in 97 of 150 unrelated FAP patients. Our findings revealed the following characteristics of the germ‐line mutations of APC: (1) the great majority of the mutations were found to truncate the APC product; (2) almost all of the mutations were located within the first half of the coding region; (3) no correlation was observed between the locations of germ‐line mutations and extracolonic manifestations in FAP patients; (4) more than 80% of base substitutions in the APC gene were from cytosine to other nucleotides, nearly one‐third of which occurred at the CpG site. Our results provide information helpful to an understanding of the APC gene and will also contribute to presymptomatic diagnosis of members in FAP families. © 1992 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380010603

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

年代:1992

数据来源: WILEY

摘要:

AbstractWe have examined a panel of 115 unrelated NF1 individuals for mutation in the 3′ region of the NF1 gene, using Southern blotting and polymerase chain reaction amplification of exons followed by single‐strand conformation polymorphism (SSCP) analysis. We found only 2 unequivocal mutations: a 571 bp deletion which removed exon 6 and resulted in a frameshift in exon 7, and a 2 bp deletion in exon 1. A third sequence variation detected by SSCP was predicted to cause a lysine‐arginine substitution in exon 6. This is a conservative change, and since the affected individual is a new mutation whose parents are not available, we cannot be sure of its biological significance. We detected mutations in at most 3% of individuals, from an analysis which covered 17% of the coding sequence by SSCP and a larger region by Southern blotting. This relative failure to detect mutations accords with the experience of others. Even allowing for the incomplete sensitivity of the methods used, the results suggest that the majority of NF1 mutations lie elsewhere in the coding sequence or outside it. © 1992 Wiley‐L

ISSN:1059-7794    

DOI:10.1002/humu.1380010604

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

年代:1992

数据来源: WILEY

摘要:

AbstractThe phenotype in therdmouse is similar to the clinical presentation of Leber congenital amaurosis (LCA) in humans. Recently a nonsense mutation in the beta subunit of the cGMP phosphodiesterase (Pdeb) gene has been defined as the cause for therdphenotype in the mouse and has raised the question as to whether mutations in the human PDEB gene might cause LCA. We have previously cloned and characterized the human homologue of the mousePdebgene and have mapped it to chromosome 4p16.3. In this study, a total of 23 LCA families of various ethnic backgrounds have been investigated. Linkage analysis using highly polymorphic (CA)nmicrosatellites has excluded the PDEB gene as a cause for LCA in 6 families. In the remaining 17 families, we have searched for mutations in the 22 exons of the PDEB gene using single‐strand gel electrophoresis (SSGE). Multiple exonic polymorphisms have been determined. However, no DNA changes in the PDEB gene have been identified in our study population which could be causative for the LCA phenotype. © 1992 Wiley‐Liss,

ISSN:1059-7794    

DOI:10.1002/humu.1380010605

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

年代:1992

数据来源: WILEY

摘要:

AbstractThe Ashkenazi Jewish population is enriched for carriers of a fatal form of Tay‐Sachs disease, a recessive inherited disorder caused by mutations in the α‐chain of the lysosomal enzyme β‐hexosaminidase A. Approximately 20% of the Ashkenazi carriers harbor a splice junction defect while about 78% bear a 4 base pair (bp) insertion. However, the Ashkenazi Jewish patient used in the original description of the 4 bp insertion carried this lesion in only 1 allele and was negative for the splice junction mutation. We cloned the insertion negative allele and by sequence analysis of the exons found a point mutation in exon 11 that results in substitution of Trp392with a premature termination codon. Nine Ashkenazi Jewish carriers that tested negative for the major and minor mutations as well as for a lesion causing an adult form of Tay‐Sachs disease did not carry the base change defect, suggesting that it may be a recent and/or rare mutation. This finding also indicates that screening the Ashkenazi population solely by recombinant DNA methods for the splice junction, 4 bp insertion, and adult mutations may result in occasional false negatives. © 1992 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380010606

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

年代:1992

数据来源: WILEY

摘要:

AbstractHereditary protein C (PC) deficiency is usually associated with a high risk of thrombosis. We report the results of a study undertaken to screen for molecular defects in families with hereditary quantitative PC deficiency. Using a strategy combining polymerase chain reaction amplification of selected gene fragments, denaturing gradient gel electrophoresis of the amplification products, and direct sequencing of fragments with altered melting behavior, we studied the PC gene exons and exon/intron junctions of subjects with hereditary type I PC deficiency. Computer simulation of DNA melting was used to design several sets of primers, each containing a GC‐clamp, permitting the complete analysis of each amplified exon sequence. Using this procedure, we identified two previously undescribed mutations located in exon VII: a C‐to‐T substitution generating a nonsense codon in place of Arg 157 in the mature PC and a G‐to‐A substitution converting Arg 178 to GIn. The two mutations were detected in, respectively, 3 and 2 apparently independent families. This strategy is therefore a valuable tool for screening patients, and the results emphasize its advantages over plasma assays in individuals with a family history of thrombosis. © 1992 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380010607

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

年代:1992

数据来源: WILEY

ISSN:1059-7794    

DOI:10.1002/humu.1380010608

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

年代:1992

数据来源: WILEY

ISSN:1059-7794    

DOI:10.1002/humu.1380010609

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

年代:1992

数据来源: WILEY

ISSN:1059-7794    

DOI:10.1002/humu.1380010610

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

年代:1992

数据来源: WILEY

ISSN:1059-7794    

DOI:10.1002/humu.1380010611

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

年代:1992

数据来源: WILEY