Mutations in the Cx26/GJB2 gene account for a large proportion of pre-lingual hearing impairment with a prevalence up to 50% in autosomal recessive cases and a still undefined prevalence in sporadic cases. Ninety-four subjects affected by non-syndromal sensorineural hearing impairment (NSHI) were enrolled in the study. The patients had either a family history of childhood hearing deficit or represented sporadic cases. The risk of an acquired cause of the deficit has been carefully excluded. Audiological characteristics were investigated. Cx26 mutations were found in 50% of subjects. Seventy-three per cent of mutations in this gene were 35delG, with significant geographical variations. In 7% of the putative Cx26 alleles no mutations were detected either in the coding region or in the non-coding exon 1. Cx26 hearing impairment involves all frequencies, is of variable severity, and is very rarely progressive and most frequently symmetrical between the two ears. The high occurrence of this type of pre-lingual hearing impairment argues for modification of the protocols used to investigate the aetiology of childhood hearing impairment. Early screening for Cx26 mutations in all patients with non-syndromal familial and sporadic permanent childhood hearing impairment seems justified.
This is the first report on the molecular analysis of large VHL alterations. The results of our study and the complete characterization of a large deletion lead to the hypothesis that an Alu-mediated mechanism may be responsible for the common occurrence of large alterations in the VHL gene.
Communicated by Haig H. Kazazianvon Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome predisposing to the development of retinal and central nervous system haemangioblastomas, pheochromocytomas, renal and pancreatic cancer. In the course of a molecular analysis conducted to detect germline mutations of this gene in von Hippel-Lindau patients and individuals affected by sporadic tumors, we have identified a case of somatic mosaicism in the asymptomatic mother of a VHL patient who was subsequently diagnosed with pheochromocytoma. This is the first report providing molecular evidence of somatic mosaicism in von Hippel-Lindau disease. Mosaicism could provide some genetic explanation for the clinical heterogeneity and variable severity of the VHL phenotype, and should be considered, as a possible event when evaluating sporadic cases of VHL or patients with isolated VHL-related tumors.
SummaryMutational inactivation of the VHL gene is the cause of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome predisposing to haemangioblastomas, pheochromocytomas and clear-cell renal carcinomas. The gene product (pVHL) functions as an adapter in cellular processes including cell growth and apoptosis. VHL mutation analysis was carried out in 426 unrelated subjects with phenotypes ranging from VHL syndrome, to isolated VHL-related tumours that could represent the first manifestation of the disease. A total of 111 individuals were found to carry alterations, with large deletions representing 40% of the variants. Eighteen of the 95 detected variants were novel, seemingly disease-causing mutations; their pathogenic role has been evaluated in silico for effects on protein folding and interactions. Putative regions of interaction between pVHL and proteins involved in common pathways have been identified, assessing possible implications for the presence of mutations in these regions. All new variants predicted to truncate or cause complete pVHL loss of structure were associated with phenotypes consistent with VHL type 1. Seven of the new amino acid substitutions are disease-causing mutations, one is a neutral variant, whereas the results for two remain ambiguous. Our combined molecular and in silico approach for the evaluation of putative disease-causing mutations contributes to the interpretation of the potential pathogenicity of these novel variants.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.