2E4/Kaptin (KPTN) - a candidate gene for the hearing loss locus, DFNA4

Stereocilia of the inner ear play an integral role in the mechanotransducti on of sound. Their structural support is derived from actin filaments and a ctin-binding proteins. We have identified a novel actin-binding protein, 2E 4-kaptin (KPTN), which appears to be involved in this structural network. U sing double label immunofluorescence, we now show that KPTN extends beyond the barbed ends of actin filaments at the tips of stereocilia, and using cl oned human cDNA, we mapped KPTN to chromosome 19q13.4. A combination of FIS H, radiation hybrid mapping and YAC screening localized KPTN between marker s D19S412 and NIB1805, making this gene an excellent functional and positio nal candidate for DFNA4, a form of autosomal dominant non-syndromic hearing loss. We identified a second family with inherited deafness that also maps to the DPNA4 region. To screen KPTN for deafness-causing mutations, we fir st determined its genomic structure and then completed a mutational analysi s by direct sequencing and SSCP in affected family members. Although no dea fness-causing mutations were identified in the coding region, KPTN remains an excellent candidate gene for hearing loss; by synteny, Its murine orthol ogue also remains a candidate gene for the Nijmegan waltzer (nv) mouse muta nt, which has vestibular defects and a variable sensorineural hearing loss.