The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions

Abstract

Usher syndrome type 1 (USH1) patients suffer from sensorineuronal deafness, vestibular dysfunction, and visual impairment. Several genetic loci have been linked to USH1, and four of the relevant genes have been identified. They encode the unconventional myosin VIIa, the PDZ-domain protein harmonin, and the putative adhesion receptors cadherin 23 (CDH23) and protocadherin 15 (PCDH15). We show here that CDH23 and harmonin form a protein complex. Two PDZ domains in harmonin interact with two complementary binding surfaces in the CDH23 cytoplasmic domain. One of the binding surfaces is disrupted by sequences encoded by an alternatively spliced CDH23 exon that is expressed in the ear, but not the retina. In the ear, CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the retina within the photoreceptor cell layer. Because CDH23-deficient mice have splayed stereocilia, our data suggest that CDH23 and harmonin are part of a transmembrane complex that connects stereocilia into a bundle. Defects in the formation of this complex are predicted to disrupt stereocilia bundles and cause deafness in USH1 patients.

Progressive Hearing Loss and Increased Susceptibility to Noise-Induced Hearing Loss in Mice Carrying a Cdh23 but not a Myo7a Mutation

“…Recently, Myo7a has been shown to interact with harmonin which in turn interacts with Cdh23 (Boeda et al 2002;Siemens et al 2002). All three proteins are present in the stereocilia, thus potentially placing Cdh23 and Myo7a in the same functional complex (Hasson et al 1997a;Boeda et al 2002).…”

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

“…The protocadherin LKC is associated with contact inhibition of cell proliferation, and has been suggested as a candidate TSG for colon and liver cancer (Okazaki et al, 2002). Mutations in protocadherin 15 as well as CDH23 have also been implicated in Usher syndrome (Bolz et al, 2001;Di et al, 2001;Siemens et al, 2002), as recently demonstrated in a zebrafish model Sollner et al, 2004).…”

Three-dimensional Architecture of Hair-bundle Linkages Revealed by Electron-microscopic Tomography

“…Connections of a similar form, termed ankle links, occur transiently during the development of mammalian cochlear hair cells. Among several proteins whose deficiency produces Usher Syndrome, three have been proposed to constitute the ankle links: cadherin 23 (Di Palma et al 2001;Boeda et al 2002;Siemens et al 2002), the very large G-protein- In most receptor organs of the inner ear and lateralline system, mechanical stimuli representing sounds, accelerations, or water movements are initially conveyed to the kinocilium by an extracellular accessory structure. Connections of the second type, kinociliary links, then transmit these stimuli to the five longest stereocilia (Hillman and Lewis 1971).…”