Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5

Abstract

In a consanguineous Turkish family diagnosed with autosomal recessive nonsyndromic hearing impairment (arNSHI), a homozygous region of 47.4 Mb was shared by the two affected siblings on chromosome 6p21.1-q15. This region contains 247 genes including the known deafness gene MYO6. No pathogenic variants were found in MYO6, neither with sequence analysis of the coding region and splice sites nor with mRNA analysis. Subsequent candidate gene evaluation revealed CLIC5 as an excellent candidate gene. The orthologous mouse gene is mutated in the jitterbug mutant that exhibits progressive hearing impairment and vestibular dysfunction. Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T4A (p. (Cys32Ter)) that segregated with the hearing loss. Further analysis of CLIC5 in 213 arNSHI patients from mostly Dutch and Spanish origin did not reveal any additional pathogenic variants. CLIC5 mutations are thus not a common cause of arNSHI in these populations. The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade. Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction. Although we demonstrate that CLIC5 is expressed in many other human tissues, no additional symptoms were observed in these patients. In conclusion, our results show that CLIC5 is a novel arNSHI gene involved in progressive hearing impairment, vestibular and possibly mild renal dysfunction in a family of Turkish origin.

Emerging biological roles of Cl− intracellular channel proteins

“…These data thus suggest that CLIC5 is required for the development and/or maintenance of glomerular endothelial cells and podocyte architecture. Consistent with this, a recent study has shown that a patient with a homozygous nonsense mutation in CLIC5 has mild renal dysfunction in addition to hearing loss (Seco et al, 2015).…”

“…Mutation analysis in humans has shown that CLIC5 is involved in progressive hearing impairment and vestibular dysfunction (Seco et al, 2015). In mouse, renal glomeruli in CLIC5-deficient mice exhibit reduced ezrin levels, broadened podocyte foot processes, as well as large vacuoles in glomerular endothelial cells that can lead to renal dysfunction under unfavorable genetic or environmental conditions (Wegner et al, 2010).…”

“…The latest addition to the list was CLIC6 (Friedli et al, 2003), but its high molecular mass (∼72 kDa) makes it an atypical member whose function remains unknown. Rarely occurring mutations in CLIC2 and CLIC5 have been associated with heart disease and deafness, respectively (Seco et al, 2015;Takano et al, 2012).…”

Navigating genetic diagnostics in patients with hearing loss

“…In 2015 and the first half of 2016, for instance, 14 additional genes were identified as causing NSHL in humans [4–17,18*], increasing the number of NSHL genes to nearly 100 (http://www.hereditaryhearingloss.org). Prior to TGE+MPS, the best genetic diagnosis for NSHL required serial gene-by-gene Sanger sequencing, a constraint that made comprehensive diagnostic testing prohibitively slow and expensive.…”

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

“…Many genes have been described to be involved in only one or a few families with HI. [3][4][5] Some exceptions are known, for example, mutations in GJB2 followed by mutations in STRC and MYO15A are the most common causes for arNSHI worldwide. [6][7][8][9] Since many genes contribute to hereditary HI, targeting all or a selection of protein-coding exons in a single experiment, as in WES, might currently be the best option for a comprehensive genetic analysis of HI individuals.…”