Alpha-tectorin involvement in hearing disabilities: one gene two phenotypes

The human alpha-tectorin (TECTA) gene has recently been cloned and proposed to be involved in autosomal dominant non-syndromic hearing impairment (NSH I) in two families linked to the DFNA12 locus. We have studied a Swedish pe digree with autosomal dominant NSHI with possible digenic inheritance of th e disease, involving locus DFNA12 in chromosome 11 and locus DFNA2 in chrom osome 1. Mutation analysis of the TECTA gene in this family has identified eight nucleotide substitutions indicating that TECTA is highly polymorphic. One of the changes results in a cysteine to serine (C1057 S) mutation, in the zonadhesin domain of TECTA; this segregates with the disease haplotype on chromosome 11 and is not present in a control population. The mutation r esults in the replacement of a cysteine in one of the repeats of the zonadh esin/Von Willebrand domain of the protein and might cause a chang in the cr osslinking of the polypeptide. These findings add support to the involvemen t of TECTA in hearing disabilities. However, the three families carrying di fferent TECTA mutations also show phenotypic differences: the hearing loss ranges from prelingual to progressive with late onset. The explanation for the different phenotypes and some clues regarding the functions of TECTA ma y lie in the localization of the mutations in the different modules of the protein. Another possibility is that the phenotype in the Swedish family is the result of two defective genes.