Deafness, Autosomal Recessive 31

A number sign (#) is used with this entry because of evidence that autosomal recessive nonsyndromic deafness-31 (DFNB31) is caused by homozygous mutation in the whirlin gene (WHRN; 607928) on chromosome 9q32.

Clinical Features

Mustapha et al. (2002) described a consanguineous Palestinian family from Jordan in which 6 members had profound prelingual nonsyndromic hearing loss.

Tlili et al. (2005) reported a consanguineous Tunisian family in which 4 sibs had congenital profound hearing loss (greater than 90 dB) but were otherwise healthy with no dysmorphic or other abnormal findings indicative of syndromic deafness. No vestibular defects were detected.

Mapping

By homozygosity mapping in a consanguineous Palestinian family from Jordan with autosomal recessive neurosensory hearing loss, Mustapha et al. (2002) mapped a locus for the deafness (DFNB31) to chromosome 9q32-q34. A genomewide screening showed linkage to marker D9S1776 (2-point lod score of 4.98 at theta of zero). The homozygous region common to the 6 affected individuals extended between markers D9S1824 and D9S1682, a region of 15.1 cM. The murine region showing homology of synteny to the DFNB31 interval is located on chromosome 4, which contains the locus for the recessive deafness mutant 'whirler' (wi). The whirler mutation in the mouse causes, in the homozygous adult, the shaker-waltzer syndrome: deafness and circling with tossing of the head (Fleming et al., 1994). Mustapha et al. (2002) proposed that DFNB31 and whirler may result from orthologous gene defects.

Molecular Genetics

Mburu et al. (2003) pointed out that in the whirler mouse mutant, ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicated that the gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells and outer hair cells. BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein, which the authors designated whirlin. They suggested that this PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia. In affected members of the Palestinian family with nonsyndromic deafness reported by Mustapha et al. (2002), Mburu et al. (2003) identified homozygosity for an arg778-to-ter mutation in the WHRN gene (607928.0001).

In affected members of a consanguineous Tunisian family with autosomal recessive nonsyndromic deafness showing linkage to the DFNB31 region, Tlili et al. (2005) identified a homozygous frameshift mutation in the WHRN gene (607928.0006). The mutation segregated with the phenotype in the family.