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

Abstract

Stereocilia of the inner ear play an integral role in the mechanotransduction of sound. Their structural support is derived from actin filaments and actin-binding proteins. We have identified a novel actin-binding protein, 2E4-kaptin (KPTN), which appears to be involved in this structural network. Using double label immunofluorescence, we now show that KPTN extends beyond the barbed ends of actin filaments at the tips of stereocilia, and using cloned human cDNA, we mapped KPTN to chromosome 19q13.4. A combination of FISH, radiation hybrid mapping and YAC screening localized KPTN between markers D19S412 and NIB1805, making this gene an excellent functional and positional 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 DFNA4 region. To screen KPTN for deafness-causing mutations, we first determined its genomic structure and then completed a mutational analysis by direct sequencing and SSCP in affected family members. Although no deafness-causing mutations were identified in the coding region, KPTN remains an excellent candidate gene for hearing loss ; by synteny, its murine orthologue also remains a candidate gene for the Nijmegan waltzer (nv) mouse mutant, which has vestibular defects and a variable sensorineural hearing loss. Mechanotransduction of hearing is mediated through hair cells of the sensory epithelium of the inner ear (Hudspeth, 1997). These cells lie below the tectorial membrane, which oscillates in response to sound waves, displacing stereocilia and opening gated ion channels to give rise to an electrical signal. Each hair cell has a unique complement of stereocilia, varying in length and

Cochlin in the eye: Functional implications

“…Loss or aberrant mechanosensing and transduction of mechansensory signal may also be part of pathology in progressive hearing loss (Knoll et al, 2003;Ricci et al, 2006). Dysfunction or absence of any of the mechanosensing transmembrane molecules results in disruption of the network causing sensorineural degeneration in the inner ear and in the retina in Usher syndrome, another disease that leads to retinal degeneration and progressive hearing loss (Reiners et al, 2006), and other forms of progressive hearing losses such as DFNA4 and DFNB6 (Bearer et al, 2000;Mitchem et al, 2002). The extracellular matrix of apical epithelia of the inner ear plays a role in mechanosensing, and type II collagen constitutes one of the critical molecular components of ECM of apical epithelia (Goodyear and Richardson, 2002).…”

Songs My Mother Taught Me: Gene‐Environment Interactions, Brain Development and the Auditory System: Thoughts on Non‐Kin Rejection

“…Another example of epigenetic regulation leading to a disease state can be taken from data generated by my laboratory on a human deafness locus (Bearer et al 2000). We were interested in the proteins that comprise the sensory apparatus of the auditory hair cell.…”

“…Through unbiased comprehensive high-throughput screening aimed at identifying all proteins with the potential to create this apparatus, we identified several proteins present in the apparatus (Bearer, 1995;Bearer & Abraham, 1999). After expression cloning, we sequenced cDNA for one of these proteins and used the sequence to probe DNA from families with inherited deafness to find any with mutations in this gene (Bearer et al, 2000).…”

The otoferlin interactome in neurosensory hair cells: Significance for synaptic vesicle release and trans-Golgi network (Review)

“…For one syndromic hearing defect (Usher syndrome type I) the cooperation of myosin VIIa, harmonin, sans, protocadherin 15 and cadherin 23 was shown to be essentail for the organisation of sensory hair cells (16). In the non-syndromic hearing impairment DFNA4, where the primary target of mutation was found to be MYH14 (17,18), actin filaments interact with 2E4-Kaptin and in stereocilia myosin XVa together with whirlin control the development of these cells (19,20).…”