A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3

Abstract

Mapping genes for nonsyndromic hereditary hearing impairment may lead to identification of genes that are essential for the development and preservation of hearing. We studied a family with autosomal dominant, progressive, low frequency sensorineural hearing loss. Linkage analysis employing microsatellite polymorphic markers revealed a fully linked marker (D4S126) at 4p16.3, a gene-rich region containing IT15, the gene for Huntington's disease (HD). For D4S126, the logarithm-of-odds (lod) score was 3.64 at theta = 0, and the overall maximum lod score was 5.05 at theta = 0.05 for D4S412. Analysis of recombinant individuals maps the disease gene to a 1.7 million base pair (Mb) region between D4S412 and D4S432. Genes for two types of mutant mice with abnormal cochleovestibular function, tilted (tlt) and Bronx waltzer (bv), have been mapped to the syntenic region of human 4p16.3 on mouse chromosome 5. Further studies with the goals of cloning a gene for autosomal nonsyndromic hearing impairment and identifying the murine homologue may explain the role of this gene in the development and function of the cochlea.

Confirmation of genetic homogeneity of nonsyndromic low-frequency sensorineural hearing loss by linkage analysis and a DFNA6/14 mutation in a Japanese family

“…A telomeric boundary of the disease locus was estimated to be between D4S2366 and D4S2935 by another recombination observed in individual III-17. These results, with reference to previously reported data for DFNA6/14 (Lesperance et al 1995;Van Camp et al 1999), suggested that the disease of this family was associated with a new LFSNHL locus between D4S2366 and D4S2983. No mutations were found in the ten genes other than WFS1 analyzed.…”

“…The mutation site in the hydrophobic, extracytoplasmic, juxta-transmembrane region seen in this family was hitherto undescribed. This unique mutation site in our patients may be related to their milder phenotype compared with those of the six previously identified DFNA6/14 patients with WFS1 mutations (Lesperance et al 1995;Strom et al 1998). It is likely that a genotype-phenotype correlation is also applicable in the case of this disorder.…”

“…WFS is an autosomal recessive disorder characterized by diabetes inspidus, juvenile-onset diabetes mellitus, bilateral progressive optic atrophy, and deafness. WFS1 encodes wolframin, which consists of 890 amino acids with nine putative transmembrane domains, a hydrophilic amino terminus, and a hydrophobic COOH tail, as determined by hydrophobicity analysis (Lesperance et al 1995;Inoue et al 1998;Strom et al 1998). Many WFS1 mutations result in protein truncation, and some mutations result in amino acid substitutions.…”

Additional heterozygous 2507A>C mutation of WFS1 in progressive hearing loss at lower frequencies

“…Based on the audiometric configurations, we screened for the presence of TECTA and WFS1 mutations. Exons 17,18,19, and 20 of TECTA, corresponding to the zona pellucida domain of alpha-tectorin (the product of TECTA), were amplified by polymerase chain reaction (PCR), because mutations in that region lead to autosomal dominant mid-frequency SNHL. 6 The entire coding regions of WFS1 were amplified as previously described.…”

Heat shock protein 70 alters the endosome-lysosomal localization of huntingtin

“…Selective neuronal loss in the neostriatum and cortex causes choreic movement and dementia (Ross et al, 1997). The gene defective in HD is located on chromosome 4p16.3 (Lesperance et al, 1995) and is translated into huntingtin, a 350 kDa ubiquitous protein (Ide et al, 1995;Sharp et al, 1995). Moreover, increased CAG trinucleotide repeats in exon 1 lead to polyglutamine expansion in the N-terminus of huntingtin and are responsible for neurodegeneration in the HD brain (MacDonald et al, 1993, The Huntington's Disease Collaborative Research Group).…”