摘要:

AbstractTo date, over 40 different mutations in transthyretin (TTR) have been associated with amyloid deposition. The major unresolved problem is the correlation between the clinical heterogeneity and the genetic heterogeneity. For instance, whereas some mutations produce neuropathy and some give rise to cardiomyopathy, others produce vitreous opacities, the vast majority being neuropathic. Moreover, some mutations are not amyloidogenic but are responsible to hyperthyroxinemias (by virtue of the protein function in thyroid transport), whereas others are apparently nonpathogenic. The study of TTR variants is very important to the understanding of the amyloid formation process and to establish a relationship between the structure and function of the molecule. The results of current TTR mutation screening programs and their characterization are summarized. © 1995 Wiley‐Liss, I

ISSN:1059-7794    

DOI:10.1002/humu.1380050302

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

年代:1995

数据来源: WILEY

摘要:

AbstractA population of 35 Alport syndrome patients, defined by strict diagnostic criteria, was screened for mutations in 23 exons of the COL4A5 gene by SSCP analysis. Mobility shifts were observed in 12 out of 35 patients and were shown to represent genuine mutations. 9 of these were glycine substitutions in the collagenous domain (in exons 20, 25, 26, 29, 31, and 41), 2 were small deletions resulting in frameshifts (in exons 21 and 31), and one was a splice site mutation (in exon 12). © 1995 Wiley‐Liss, I

ISSN:1059-7794    

DOI:10.1002/humu.1380050303

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

年代:1995

数据来源: WILEY

摘要:

AbstractTo date, a large number of mutations causing the disease, cystic fibrosis, have been reported worldwide. Having analysed the coding sequence of a sample of cystic fibrosis (CF) patients from Russia, we have identified three novel CF mutations. Two of them, 175 del C in exon 1 and 624 del T in exon 5, are frameshift mutations, predicted to result in premature termination of the CFTR transcript. The third mutation is missense and occurs in exon 12 (D572N). The profile of mutations in this sample of Russian CF patients is particular, with two mutations in exon 13 (2143 del T and 2184 ins A), accounting for 12% of the non‐δF508 alleles. © 1995 Wiley‐Liss

ISSN:1059-7794    

DOI:10.1002/humu.1380050304

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe mutational effects at the mRNA level were investigated by RT‐PCR analysis of nine different nonsense mutations (Q39X, E60X, R75X, G542X, L719X, Y1092X, R1162X, S1196X, W1282X) and one frameshift mutation (1078delT) within the CFTR gene. With the exception of mutation R1162X, reduced mRNA levels ranging from 30% to less than 5% of the wild type have been observed. In case of the R75X and E60X mutations, the mRNA reduction was accompanied by the appearance of atypical CFTR isoforms. Single exon 3 skipping, as well as joint exon 2 and 3 skipping, was observed in lymphocyte and nasal epithelial mRNA derived from R75X alleles. The analysis of mRNA transcribed from E60X alleles revealed skipping of exon 3 (lymphocytes and nasal epithelial cells) or skipping of exons 3 and 4 (nasal epithelial cells). With the exception of the E60X mutation, no obvious tissue‐specific differences in the splicing pattern and ratios of mutation to wild‐type transcripts were detected between lymphocytes and nasal epithelial cells. In addition to aberrant splicing, the reduction of transcripts is the most common effect of nonsense and frameshift mutations within the CFTR gene. © 1995 Wiley‐L

ISSN:1059-7794    

DOI:10.1002/humu.1380050305

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

年代:1995

数据来源: WILEY

摘要:

AbstractWe have examined a panel of 21 sporadic Wilms' tumours for rearrangements in the Wilms' tumour suppressor gene, WT1. In one tumour with specific allele loss in chromosome 11pl3, a homozygous deletion in the 3′ end of the gene, encompassing exon 10 and the 3′ untranslated region, was identified. High levels of a truncated WT1 transcript, predicted to encode a polypeptide missing the fourth zinc finger were expressed in this tumour. All other samples showed normal patterns of digestion on Southern Hots. This observation confirms previous findings that large deletions in the gene occur infrequently in sporadic Wilms' tumours and that the zinc‐finger region of the encoded polypeptide is critical for correct functioning of the gene.© 1995 wiley‐L

ISSN:1059-7794    

DOI:10.1002/humu.1380050306

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

年代:1995

数据来源: WILEY

摘要:

AbstractAutosomal recessive retinitis pigmentosa (ARRP) is a degenerative disease of photoreceptors in which defects in the rhodopsin and phosphodiesterase β‐subunit (PDEB) loci have been reported. To assess the involvement of PDEB in ARRP families from Spain, we screened a panel of 19 families for linkage to markers within or close to the PDEB gene. Homozygosity was also tested in cases of consanguinity. This combined approach ruled out PDEB as the cause of the disease in all but one of the families. Molecular characterization of the gene in that family (a consanguineous pedigree) revealed a homozygous 71′bp tandem duplication in exon 1 of the affected member, the parents being heterozygous. This defect causes a frameshift mutation which leads to a premature stop codon, suggesting that this mutant allele is the underlying cause of ARRP in this patient. According to the data presented here, the PDEB gene is not the main gene responsible for ARRP, but accounts for about 5% of the cases.© 1995 wiley‐Li

ISSN:1059-7794    

DOI:10.1002/humu.1380050307

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 and nonradioactive method to screen for point mutations using the Pharmacia Phast System. In an SSCP analysis, we applied the two multiplex exon PCR kits, commonly used for the detection of deletions in Duchenne and Becker muscular dystrophy patients. The different exon bands in the multiplex SSCP pattern could be identified by running well‐characterised deletion patients in this system. Two common polymorphisms were easily identifiable and are helpful in the haplotype analysis in families. Screening of 70 patients in which no gross rearrangement was detectable with the multiplex PCR and Southern blot, resulted in the identification of 6 patients with a band shift after ‐SSCP analysis. Of these 6 band shifts, 5 were the result of a frame shift or termination mutation. The other band shift was found to be a rare polymorphism unlikely to be the cause of the patient's phenotype. Application of this technique enabled us to improve diagnosis in the families involved and will allow us to extend the search for point mutations in the remaining exons of the dystrophin gene. © 1995 Wiley‐Lis

ISSN:1059-7794    

DOI:10.1002/humu.1380050308

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

年代:1995

数据来源: WILEY

摘要:

AbstractThree new missense mutations (H15D, A83D, and A179D) and a new splicing defect (573 + 1G→A) in the 5′ splice site of intron 5 were among six mutant adenosine deaminase (ADA) alleles found in three unrelated patients with severe combined immunodeficiency disease, the most common phenotype associated with ADA deficiency. When expressed in vitro, the H15D, A83D, and A179D proteins lacked detectable ADA activity. The splicing defect caused skipping of exon 5, resulting in premature termination of translation and a reduced level of mRNA. H15D is the first naturally occurring mutation of a residue that coordinates directly with the enzyme‐associated zinc ion. Molecular modeling based on the atomic coordinates of murine ADA suggests that the D15 mutation would create a cavity or gap between the zinc ion and the side chain carboxylate of D15. This could alter the ability of zinc to activate a water molecule postulated to play a role in the catalytic mechanism. A83 and A179 are not directly involved in the active site, but are conserved residues located respectively in a helix 4 and β strand 4 of the α/β barrel. Replacement of these small hydrophobic Ala residues with the charged, more bulky Asp side chain may distort ADA structure and affect enzyme stability or folding.© 1995 wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380050309

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

年代:1995

数据来源: WILEY

摘要:

AbstractAmelogenins are an heterogenous family of proteins produced by ameloblasts of the enamel organ during tooth development. Disturbances of enamel formation occur in amelogenesis imperfecta, a clinically heterogenous group of inherited disorders characterised by defective enamel biomineralisa‐tion. 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). We have identified three families exhibiting AIH1 and screened the AMGX gene for mutations using single‐strand conformational polymorphism analysis and DNA sequencing. 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. 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. © 1995 W

ISSN:1059-7794    

DOI:10.1002/humu.1380050310

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

年代:1995

数据来源: WILEY

摘要:

AbstractWe describe a nonisotopic single‐tube polymerase chain reaction (PCR) multiplex system that detects 10 of the more common cystic fibrosis (CF) mutations (ΔF508, ΔI507, V520F, G551D, G542X, R553X, R117H, 621 + lG→T, N1303K, A455E). The use of this method detects approximately 90% of the CF alleles in the British population. Five exons of the CF gene are amplified simultaneously by PCR, followed by an overnight triple enzyme restriction digest, and then resolved by high‐resolution gel acrylamide electrophoresis. © 1995 Wiley

ISSN:1059-7794    

DOI:10.1002/humu.1380050311

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

年代:1995

数据来源: WILEY