摘要:

AbstractSeveral investigators have reported germline mutations of theAPCgene in patients with familial adenomatous polyposis (FAP) as well as somatic mutations in tumors developed in digestive organs (stomach, pancreas, colon, and rectum). Those results provide evidence that inactivation of theAPCgene plays a significant role in FAP and in sporadic tumors of these tissues.APCmutations have led to some interesting observations. First, the great majority of the mutations found to date would result in truncation of theAPCproduct. Second, almost all the mutations have occurred within the first half of the coding sequence, and somatic mutations in colorectal tumors are further clustered in a particular region called MCR (mutation cluster region). Third, most identified point mutations in theAPCgene are transitions from cytosine to other nucleotides. Fourth, the location of germ‐line mutations tends to correlate with the number of colorectal polyps in FAP patients. Furthermore, inactivation of both alleles of theAPCgene seems to be required as an early event to develop most of adenomas and carcinomas in the colon and rectum as well as some of those in the stomach. © 1993 Wiley‐Liss,

ISSN:1059-7794    

DOI:10.1002/humu.1380020602

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

年代:1993

数据来源: WILEY

摘要:

AbstractA number of mutations in the X‐chromosomal human iduronate‐2‐sulphatase gene have now been identified as the primary genetic defect leading to the clinical condition known as Hunter syndrome or mucopolysaccharidosis type II. The mutations that are tabulated include different deletions, splice‐site and point mutations. From the group of 319 patients thus far studied by Southern analysis, 14 have a full deletion of the gene and 48 have a partial deletion or other gross rearrangements. All patients with full deletions or gross rearrangements have severe clinical presentations. Twenty‐nine different “small” mutations have so far been characterised in a total of 32 patients. These include 4 nonsense and 13 missense mutations, 7 different small deletions from 1 to 3 bp, with most leading to a frameshift and premature chain termination, and 5 different splice‐site mutations also leading to small insertions or deletions in the mRNA. A 60 bp deletion, that results from a new donor splice‐site, has been observed in five unrelated patients with relatively mild clinical phenotypes. This information will not only be useful for MPS II patient and carrier diagnosis, but also will aid in the understanding of the structure and function of iduronate‐2‐sulphatase, and possibly in correlating genotype with phenotype.

ISSN:1059-7794    

DOI:10.1002/humu.1380020603

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

年代:1993

数据来源: WILEY

摘要:

AbstractA patient with hydrops fetalis caused by β‐glucuronidase deficiency was found to be homozygous for a C to T transition at nucleotide position 672 in his cDNA. Genomic analysis showed the presence of pseudogenes for the β‐glucuronidase gene. After separation of PCR products of the gene and the pseudogenes it was shown that the patient and his father were heterozygous for the C‐T 672 transition and the mother did not carry the mutation. © 1993 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380020604

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

年代:1993

数据来源: WILEY

摘要:

AbstractFour prior mutations have been reported in three patients with β‐glucuronidase deficiency mucopolysaccharidosis (MPS VII), none of whom had the severe, infantile, hydropic form of the disease. We identified two mutations in the first reported case of nonimmune hydropic MPS VII whose cultured fibroblasts had60 hr) and a specific activity 35% of wild‐type enzyme. The R611W enzyme had a t0.5of 20 hr and no detectable catalytic activity. The t0.5of enzyme produced on cotransfection with A354V and R611W was nearly identical to that of A354V alone. Mutant enzyme expressed in transfected murine MPS VII cells gave similar residual activities relative to the wild‐type enzyme. In COS cells, the A354V monomers formed mixed tetramers with coexpressed rat monomers, but the product of R611W did not. The higher than expected activity, both in COS cells and in murine MPS VII cells expressing A354V, provides further evidence that overexpression can partially correct some β‐glucuronidase mutations, apparently by driving the folding reaction of monomers or the assembly into tetramers by mass actio

ISSN:1059-7794    

DOI:10.1002/humu.1380020605

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

年代:1993

数据来源: WILEY

摘要:

AbstractLeukocyte adhesion deficiency (LAD) is an inherited immunodeficiency disorder caused by CD18 subunit abnormality dependent defective expression of β2integrins on the surface of leukocytes. On analysis of the CD18 molecular defect in a female Japanese patient with a severe deficiency LAD phenotype, neither CD11a nor CD18 molecules could be detected on the patient's EBV‐transformed B lymphoblastoid cell line. The mRNA of the patient's B cells was normal in size, but was diminished in quantity, to approximately half normal levels. Sequencing of the CD18 cDNA of the patient revealed a C605to T transition, resulting in a Pro178→ Leu substitution. This was heterozygous in the genomic DNA, and shown to be of maternal origin by family study. Only a few transcripts from the other allele without the Pro178→ Leu mutation were detectable. Northern blot analysis revealed reduced CD18 mRNA levels, not only in the patient, but also in the father and brother. These results indicate that our case is a compound heterozygote with two different mutant alleles: one causing a single amino acid substitution and the other causing defective expression of mRNA. © 1993 Wiley‐

ISSN:1059-7794    

DOI:10.1002/humu.1380020606

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

年代:1993

数据来源: WILEY

摘要:

AbstractPrevious data suggested an elevated rate of polymorphism in Alu sequences. Direct genomic sequencing was performed on five Alu repeats in the factor IX gene in at least 20 unrelated males of European and Asian descent (40 kb total). In these Alu sequences, the estimated rate of polymorphism in Caucasians (HE= 7.1 × 10−4; HN= 4.5 × 10−4) is similar to previously examined nonrepetitive sequences in the factor IX gene, and about twofold lower than previous estimates of the average rate of polymorphism for the X‐chromosome which utilized random genomic clones to detect RFLPs. The aggregate data on the rate of polymorphism in Alu sequences suggest that mutations due to gene conversions at these sites are infrequent. © 1993 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380020607

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

年代:1993

数据来源: WILEY

摘要:

AbstractWe have identified the mutations in the hypoxanthine phosphoribosyltransferase (hprt) gene in five patients with the Lesch Nyhan syndrome (LN) by direct sequencing of hprt cDNA and genomic DNA. Three of the mutations affect splicing of exons 1, 2, and 9, respectively, while two are missense mutations in exons 3 and 8. All 5 mutations result in profound hprt deficiency as measured in fibroblast lysates. However, small differences in the clinical phenotype are seen between the patients. All these mutations are unique and have not been reported previously. © 1993 Wiley‐Liss, I

ISSN:1059-7794    

DOI:10.1002/humu.1380020608

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

年代:1993

数据来源: WILEY

摘要:

AbstractGermline mutations in patients with familial adenomatous polyposis were analyzed by polymerase chain reaction (PCR) amplification of the adenomatous polyposis coli gene. PCR products from heterozygous patients for deletions of this gene formed four distinct bands on polyacrylamide gel electrophoresis. The four fragments were subsequently purified and both strands of each fragment were directly sequenced, using an automated DNA sequencer and the same primers as those for PCR amplification. It was found that the two slower migrating fragments were “bulge” heteroduplexes, while the other two were homoduplexes made up of two wild‐type strands and two deletion‐mutant strands, respectively. The sites of deletions in the adenomatous polyposis coli gene could be exactly determined in four of the five patients. In an attempt to identify deletion‐carriers of familial adenomatous polyposis at the presymptomatic stage, a family study was also carried out, and two children were found to have the same mutations as those of their affected parents. The direct sequencing of heteroduplex fragments generated during PCR amplification is a potentially useful method for detecting mutations of not only the adenomatous polyposis coli gene but also many other genes of genetic diseases. © 1993 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380020609

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

年代:1993

数据来源: WILEY

ISSN:1059-7794    

DOI:10.1002/humu.1380020610

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

年代:1993

数据来源: WILEY

ISSN:1059-7794    

DOI:10.1002/humu.1380020611

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

年代:1993

数据来源: WILEY