Deafness, Autosomal Recessive 15

A number sign (#) is used with this entry because autosomal recessive deafness-15 (DFNB15), also known as DFNB72 or DFNB95, is caused by homozygous mutation in the GIPC3 gene (608792) on chromosome 19p13.

Description

This form of autosomal recessive deafness is sensorineural and nonsyndromic, and shows prelingual onset (summary by Charizopoulou et al., 2011).

Clinical Features

Van Camp et al. (1997) and Chen et al. (1997) reported a consanguineous Indian family with prelingual stable nonsyndromic deafness.

Ain et al. (2007) studied 3 consanguineous Pakistani families with prelingual-onset bilateral nonprogressive hearing loss that severely affected development of oral-auditory speech and communication. Pure-tone audiometric testing revealed moderate to severe hearing loss in 2 of the families and profound deafness in the third family. There were no obvious signs of vestibular dysfunction, retinitis pigmentosa, or other syndromic phenotypes cosegregating with hearing loss in the 3 families.

Charizopoulou et al. (2011) reported a Dutch family with prelingual onset of nonsyndromic bilateral hearing impairment. The deafness locus for this family was designated DFNB95.

Mapping

Van Camp et al. (1997) and Chen et al. (1997) reported that a genomewide search in an Indian family (DFNB15) with prelingual stable nonsyndromic deafness showed homozygosity by descent on chromosomes 3q and 19p. Both regions generated a lod score of 2.78, the maximum attainable in this family. They concluded that the disorder was due to a mutation at 3q21.3-q25.2 and/or 19p13.3-p13.1. Adato et al. (1999) discussed possible digenic inheritance of deafness in families they studied and pointed out that one of the loci, 3q21.3-q25.2, included the Usher syndrome type 3 locus (USH3; 276902) and the other, 19p13.3-p13.1, included the MYO1F gene (601480), which is a member of the unconventional myosin group.

Ain et al. (2007) performed linkage analysis in 3 consanguineous Pakistani families segregating nonsyndromic hearing loss. In 1 family (PKDF219), which was later found to segregate Perrault syndrome-3 (PRLTS3; 614129), they obtained maximum 2-point lod scores of 3.01 at marker D19S1034. Linkage analysis of the 2 other families identified strong evidence (3.85 and 3.71 at marker D19S894) for another locus on chromosome 19p13.3, which was designated DFNB72.

Molecular Genetics

In affected members of an Indian family, previously reported by Van Camp et al. (1997) and Chen et al. (1997), and a Dutch family, both with autosomal recessive sensorineural deafness of prelingual onset (DFNB15 and DFNB95, respectively), Charizopoulou et al. (2011) identified 2 different homozygous mutations in the GIPC3 gene on chromosome 19p13 (L262R; 608792.0001 and W301X; 608792.0002, respectively). The gene was chosen for study after Charizopoulou et al. (2011) found that a mutation in the murine gene Gipc3 was responsible for autosomal recessive deafness in the mouse (see ANIMAL MODEL).

Rehman et al. (2011) identified 7 different homozygous mutations, including 1 frameshift and 6 missense mutations, in the GIPC3 gene (see, e.g., 601869.0003-601869.0005) in affected members of 7 unrelated consanguineous Pakistani families with autosomal recessive nonsyndromic deafness, including the 2 families with DFNB72 previously reported by Ain et al. (2007).

Animal Model

By positional cloning, Charizopoulou et al. (2011) identified a homozygous G115R mutation in the Gipc3 gene as causative for autosomal recessive early-onset age-related hearing loss-5 (ahl5) in the mouse. Mutation in this gene was also found to underlie the murine juvenile audiogenic monogenic seizure (jams1) phenotype, in which affected mice show seizure susceptibility early in life that disappears with age. The G115R mutation caused a reduction of the Gipc3 protein. Histopathologic studies of mutant mice showed irregular structure of the stereocilia bundle of outer and inner hair cells, and late-onset degeneration of the organ of Corti starting at the base and progressing towards the apex. Concomitantly, the spiral ganglion exhibited a severe loss of neurons that was most obvious at the base and the mid-apical region of the cochlea. These data suggest that Gipc3 is required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion. Mutant mice showed defects in mechanotransduction in both inner and outer hair cells that was associated with defects in potassium channel activity. Audiogenic seizure susceptibility and later resistance correlated with increased and subsequent decline of the amplitude of audiogenic brainstem responses. In wildtype mice, Gipc3 was localized to the cytoplasm of the inner and outer hair cells, the cochlear spiral ganglion neurons, and the vestibular hair cells and vestibular ganglion neurons.