Deafness, Autosomal Recessive 76

A number sign (#) is used with this entry because autosomal recessive deafness-76 (DFNB76) is caused by homozygous mutation in the SYNE4 gene (615535) on chromosome 19q13.

Clinical Features

Horn et al. (2013) reported 6 patients from 2 unrelated consanguineous Iraqi Jewish families with autosomal recessive deafness. Affected individuals had onset of progressive high frequency hearing impairment between birth and 6 years of age. The hearing loss was severe at high frequencies by adulthood.

Inheritance

The transmission pattern of DFNB76 in the families reported by Horn et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of 2 consanguineous Iraqi Jewish families with autosomal recessive hearing loss, Horn et al. (2013) found linkage to a 5.4-Mb region on chromosome 19q13 (lod score of 3.2). The locus was designated DFNB76.

Molecular Genetics

In 6 patients from 2 unrelated consanguineous Iraqi Jewish families with autosomal recessive deafness, Horn et al. (2013) identified a homozygous truncating mutation in the SYNE4 gene (c.228_229delAT; 615535.0001). The mutation was found by homozygosity mapping followed by Sanger sequencing of genes within the interval. In vitro functional expression studies showed that the mutant proteins resulting from the deletion had abnormal intracellular localization within the cytoplasm. The SYNE4 gene is normally expressed in mechanosensory hair cells where it localizes to the nuclear envelope. Horn et al. (2013) suggested that the mutation compromised the motility of outer hair cells.

Animal Model

Horn et al. (2013) found that Nesp4 -/- mice were born at the expected mendelian ratio, appeared normal, and showed no behavioral abnormalities. Histochemical analysis revealed no abnormalities in secretory epithelial tissues, including salivary and mammary glands and exocrine pancreas. Nursing pups of Nesp4 -/- dams gained weight at a normal rate, indicating absence of mammary dysfunction. Auditory brainstem responses revealed that Nesp4 -/- mice, but not Nesp +/- mice, developed hearing loss that progressed to all frequencies by postnatal day 60. At postnatal day 0, Nesp4 -/- cochlea appeared normal; however, with onset of detectable hearing, Nesp4 -/- outer hair cells showed progressive degeneration, from the base to the apex, with concomitant redistribution of nuclei from the base of outer hair cells to a more apical position. Disruption of the inner hair cells was delayed to postnatal day 180. Sun1 -/- animals showed a similar overall phenotype, with hearing loss and degeneration of cochlear outer hair cells. Sun1 -/- mice also showed loss of Nesp4 from the nuclear envelope of cochlear outer hair cells. Horn et al. (2013) concluded that the LINC proteins NESP4 and SUN1 are necessary for viability and normal morphology of cochlear outer hair cells and maintenance of normal hearing.