Deafness DFNB110 associated with a human MAP3K1 recessive variant recapitulates hearing loss of Map3k1 kinase deficient mice

Abstract Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many genes causing rare forms of deafness remain to be discovered. Microarrays and exome sequencing were used to study a consanguineous Pakistani family segregating nonsyndromic deafness in two sibships. A 1.2 Mb locus (DFNB110) 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 MAP3K1 co-segregated with nonsyndromic deafness. MAP3K1 phosphorylates serine and threonine or tyrosine and functions in a signaling pathway where pathogenic variants of HGF, MET and GAB1 were previously reported to be associated with human deafness DFNB39, DFNB97 and DFNB26, respectively. Single-cell transcriptome data obtained from mouse cochlea mRNA show Map3k1 expression and its associated signaling partners necessary for hearing. Computational modeling of p.(Arg1487His) predicts a subtle structural alteration consistent with the limited DFNB110 phenotype in contrast to the pleiotropic phenotype of dominant MAP3K1 variants causing Disorders of Sex Development 46,XY sex-reversal and the reported syndromic deafness phenotype of two different protein truncating recessive variants of mouse Map3k1.