A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C

Abstract

Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)1. Six different USH1 loci have been reported. So far, only MYO7A (USH1B), encoding myosin VIIA, has been identified as a gene whose mutation causes the disease. Here, we report a gene underlying USH1C (MIM 276904), a USH1 subtype described in a population of Acadian descendants from Louisiana and in a Lebanese family. We identified this gene (USH1C), encoding a PDZ-domain-containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas. In patients we found a splice-site mutation, a frameshift mutation and the expansion of an intronic variable number of tandem repeat (VNTR). We showed that, in the mouse inner ear, only the sensory hair cells express harmonin. The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region. As several of these transcripts were absent from the eye, we propose that USH1C also underlies the DFNB18 form of isolated deafness.

USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses

“…Mutations in the unconventional myosin MYO7A cause USH1B (MIM 276903 14 ) and in two unique cases also atypical USH phenotype similar to that of USH3. 15 Mutations in the PDZ-domain-containing protein, harmonin, cause USH1C (MIM 276904) 16,17 . PDZ-domains are proteinprotein interaction modules that allow the binding to and clustering of specific membrane-associated proteins, such as receptors and ion channels.…”

RTEL1, une hélicase de l’ADN essentielle à la stabilité du génome

“…Il est à noter que les domaines présents dans la partie carboxy-terminale de RTEL1 sont apparus au cours de l'évolution chez les vertébrés (Figure 4). De plus, deux domaines Harmonin [32] ont été identifiés dans RTEL1 [16]. Ces domaines, localisés en aval du signal de localisation nucléaire, pourraient permettre l'interaction avec des partenaires qui restent à identifier.…”

Listen to your gut: Using adhesion to shape the surface of functionally diverse epithelia

“…[40][41][42][43][44][45] Molecular mechanisms underpinning the various forms of Usher Syndrome have been the focus of extensive investigations for many years, and insights offered by these studies have illuminated our understanding of the mechanotransduction process. 46 Whereas most tip-link and IMAC components are expressed from different genes, USH1C represents the only component common to both complexes.…”