A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin Is Essential for Outer Hair Cell Function

Abstract

Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to the pejvakin gene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the human pejvakin gene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, the pejvakin allele described here introduces a premature stop codon, causes outer hair cell defects, and leads to progressive hearing loss. We also identified a novel allele of the human pejvakin gene in an Iranian pedigree that is afflicted with progressive hearing loss. Our findings suggest that the mechanisms of pathogenesis associated with pejvakin mutations are more diverse than previously appreciated. More generally, our findings demonstrate that recessive screens in mice are powerful tools for identifying genes that control the development and function of mechanosensory hair cells and cause deafness in humans, as well as generating animal models for disease.

Parallel signatures of sequence evolution among hearing genes in echolocating mammals: an emerging model of genetic convergence

“…The positions of protein domains were taken from literature sources (Kurima et al, 2002;Delmaghani et al, 2006;Schwander et al, 2007) and confirmed using SMART (Schultz et al, 1998).…”

“…All three genes encode proteins that are expressed in the cochlea and implicated in mammalian hearing, and all have mutant forms that have been linked to non-syndromic hearing loss in humans and/or mice. The proteins Tmc1 and Pjvk have vital roles in hair cell development and function, respectively, whereas Prestin is thought to specifically drive the motility of the outer hair cells on the basilar membrane (Zheng et al, 2000;Marcotti et al, 2006;Schwander et al, 2007).…”

“…For Pjvk, the primers amplified a region (corresponding to human exons 5 to 6) that contains the functionally important putative nuclear localisation signal and zinc-binding motif (Delmaghani et al, 2006). This region also contains a premature stop codon in mutant mice (Schwander et al, 2007).…”

“…Pjvk (also known as Dfnb59) encodes a protein called pejvakin. Missense and stop mutations in the human form have both been linked to deafness-in the former case caused by auditory neuropathy (Delmaghani et al, 2006)-whereas in mice, premature stop codons disrupt hair cell activity and also cause vestibular defects (Schwander et al, 2007).…”

Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

“…66 Pejvakin possibly has an important role in the cell signaling of hair cells and sensory neurons. 67,68 The 352-amino-acid pejvakin protein is translated from a 5 kb cDNA.…”