Deafness DFNB128 Associated with a Recessive Variant of Human Recapitulates Hearing Loss of -Deficient Mice

Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 Mb locus (DFNB128) on chromosome 5q11.2 encompassing six genes was identified. In one of the two sibships of this family, a novel homozygous recessive variant NM_005921.2:c.4460G>A p.(Arg1487His) in the kinase domain of co-segregated with nonsyndromic deafness. There are two previously reported -kinase-deficient mouse models that are associated with recessively inherited syndromic deafness. phosphorylates serine and threonine and functions in a signaling pathway where pathogenic variants of , , and were previously reported to be associated with human deafness , , and , respectively. Our single-cell transcriptome data of mouse cochlea mRNA show expression of and its signaling partners in several inner ear cell types suggesting a requirement of wild-type for normal hearing. In contrast to dominant variants of associated with Disorders of Sex Development 46,XY sex-reversal, our computational modeling of the recessive substitution p.(Arg1487His) predicts a subtle structural alteration in , consistent with the limited phenotype of nonsyndromic deafness.