Deafness, Autosomal Recessive 103

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-103 (DFNB103) is caused by homozygous mutation in the CLIC5 gene (607293) on chromosome 6p21. One such family has been reported.

Clinical Features

Seco et al. (2015) reported 2 sibs, born of consanguineous Turkish parents, with early-onset nonsyndromic sensorineural deafness. The hearing impairment was probably not congenital, as both children had evidence of normal hearing at ages 7 to 9 months and 3 months, respectively. The hearing loss initially affected mid and high frequencies, but progressed to a severe/profound hearing loss affecting all frequencies. The audiogram was downsloping. Both individuals also showed vestibular areflexia during the rotary test at ages 16 and 11 years. One affected sib showed some evidence of mild renal dysfunction, which Seco et al. (2015) noted should be followed to determine if it is indeed an unrelated nephropathy or if it is linked with the mutation. (Seco et al. (2015) designated the disorder in this family autosomal recessive deafness-102, but this designation had already been given to another form of deafness; see 615974).

Inheritance

The transmission pattern of nonsyndromic sensorineural deafness in the family reported by Seco et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Turkish parents, with early-onset autosomal recessive deafness-103, Seco et al. (2015) identified a homozygous truncating mutation in the CLIC5 gene (C32X; 607923.0001). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. Screening for mutations in the CLIC5 gene in over 200 mostly Dutch or Spanish probands with hearing impairment did not identify any other mutations. Seco et al. (2015) noted that the phenotype was similar to that observed in the 'Jitterbug' mouse mutant, which results from a recessive null Clic5 allele (see ANIMAL MODEL).

Animal Model

The 'Jitterbug' (jbg/jbg) mutant mouse is an autosomal recessive phenotype characterized by overt head-bobbing and circling behavior with an inability to swim, indicating vestibular dysfunction. Mutant mice also show hearing loss that progresses to complete deafness. Gagnon et al. (2006) found that 12-month-old jbg/jbg mice had severe degeneration of the organ of Corti and a reduced density of spiral ganglion cells compared to controls. Vestibular hair cells showed progressive degeneration, first affecting the outer hair cells and later affecting the inner hair cells. Jbg/jbg mutant mice also showed emphysema-like lung pathology with a progressive enlargement of alveolar spaces. Linkage analysis and candidate gene analysis identified a homozygous intragenic deletion in the Clic5 gene resulting in a truncated protein as responsible for the phenotype. Studies of wildtype mouse embryos showed Clic5 expression in the basal region of the hair bundle of the inner ear. During cochlear development, Clic5 was closely associated with microvilli on the apical surfaces of interdental cells and columnar epithelial cells of Kolliker's organ and with stereocilia of inner and outer hair cells. The pattern of expression matched that of radixin (RDX; 179410), suggesting that CLIC5 associates with radixin in hair cell stereocilia and may help form or stabilize connections between the plasma membrane and the cytoskeletal filamentous actin core.