Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness

Abstract

We have recently shown that USH1C underlies Usher syndrome type 1c (USH1C), an USH1 subtype characterized by profound deafness, retinitis pigmentosa, and vestibular dysfunction. USH1C encodes a PDZ-domain-containing protein, harmonin. Eight different Ush1c transcripts were identified in the mouse inner ear. Moreover, transcripts containing seven alternatively spliced exons (A-F, G/G) were found to be expressed in the inner ear, but not in the eye. These findings suggested that mutations involving USH1C might also be the cause of DFNB18, a form of non-syndromic deafness, which maps to a chromosomal region that includes USH1C. We screened 32 Chinese multiplex families with non-syndromic recessive deafness for USH1C mutations. In one family, congenital profound deafness without RP was associated with a C to G transversion in the alternatively spliced exon D, predicting an arginine to proline substitution at codon 608 in the proline-, serine- and threonine-rich region of harmonin. We also screened 320 deaf probands from other ethnic background and found three who were heterozygous for changes in the alternately spliced exons including Gly431Val in exon B, Arg620Leu and Arg636Cys in exon D. None of these mutations were detected in DNA from 200 control subjects with normal hearing including 110 Chinese. We also screened 121 non-Acadian probands with type 1 Usher syndrome. None carried any mutations in these exons of USH1C. Our findings show that USH1C mutations can also cause non-syndromic deafness and that some harmonin isoforms are specifically required for inner ear function.

Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells

“…Hair bundle disorganisation has since been reported in the deaf circler 2J mouse mutant, which lacks harmonin b isoforms (Johnson et al, 2003). Also, almost all DFNB18 patients carry mutations in USH1C that selectively affect the harmonin b subclass (Ouyang et al, 2002). Moreover, ultrastructural studies have recently established that cadherin 23 is a component of both interstereocilia and kinociliary links of the growing hair bundle (Michel et al, 2005) (see Fig.…”

“…Mutations in four of the USH1 genes have also been reported to cause isolated recessive (DFNB) or dominant (DFNA) forms of deafness: DFNB2 and DFNA11 (USH1B) (Liu et al, 1997a;Liu et al, 1997b;Weil et al, 1997), DFNB18 (USH1C) (Ahmed et al, 2002;Ouyang et al, 2002), DFNB12 (USH1D) (Bork et al, 2001) and DFNB23 (USH1F) (Ahmed et al, 2002). The mutations causing these isolated forms of deafness are usually expected to be less deleterious for the protein activities than those observed in USH1 patients.…”

Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15

“…For example, a mutation at the DFNB18 locus in an exon normally spliced out in the retinal cells may give rise to isolated deafness in the absence of retinal dysfunction. 41 Perhaps the DFNB23 alleles occur in exons not expressed in the eye. Recently, a novel Usher locus (USH1H) has been mapped to chromosome 15q22-23, which also overlaps the nonsyndromic deafness locus DFNB48, raising the possibility that Usher and nonsyndromic deafness may be caused by nonsense and missense mutation at the same gene.…”

Usher syndrome type 1 due to missense mutations on bothCDH23 alleles: investigation of mRNA splicing

“…It has been estimated that approximately 1.6% of disease-causing missense mutations in human genes probably affect mRNA splicing [Krawczak et al, 2006]. For three genes underlying Usher syndrome type 1, there is a clearcut genotype-phenotype correlation, with truncating mutations causing the syndromic phenotype, while missense/in-frame alterations lead to non-syndromic deafness (USH1C and USH1C/DFNB18, CDH23 and USH1D/DFNB12, PCDH15 and USH1F/DFNB23; [Ahmed et al, 2003;Ahmed et al, 2002;Bitner-Glindzicz et al, 2000;Bolz et al, 2001;Bork et al, 2001;Ouyang et al, 2002]). The four CDH23 missense mutations investigated herein have been described in homozygous state in patients with USH1.…”