Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1 -Deficient Mice

• Published in: Genes 2024-07, Vol.15 (7), p.845
• Main Authors: Faridi, Rabia, Yousaf, Rizwan, Inagaki, Sayaka, Olszewski, Rafal, Gu, Shoujun, Morell, Robert J, Wilson, Elizabeth, Xia, Ying, Qaiser, Tanveer Ahmed, Rashid, Muhammad, Fenollar-Ferrer, Cristina, Hoa, Michael, Riazuddin, Sheikh, Friedman, Thomas B
• Format: Article
• Language: English
• Subjects: Amino acids; Animal models; Animals; c-Met protein; Chromosome 5; Cochlea; Consanguinity; Deafness; Deafness - genetics; Disease Models, Animal; domain; Exome Sequencing; family; Female; Gene expression; Gene mutations; Genes; Genes, Recessive; Genetic screening; Genotype & phenotype; Hearing loss; Hearing Loss - genetics; homozygosity; Humans; Informed consent; Inner ear; Kinases; loci; Male; MAP Kinase Kinase Kinase 1 - genetics; MAP Kinase Kinase Kinase 1 - metabolism; Medical screening; Mice; microarray technology; mutants; Pedigree; phenotype; Phenotypes; Proteins; Review boards; serine; Sex reversal; Signal transduction; Software; threonine; transcriptome; Transcriptomes; Whole genome sequencing
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes15070845

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.