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Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1 -Deficient Mice.
- Source :
- Genes; Jul2024, Vol. 15 Issue 7, p845, 15p
- Publication Year :
- 2024
-
Abstract
- 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 MAP3K1 co-segregated with nonsyndromic deafness. There are two previously reported Map3k1-kinase-deficient mouse models that are associated with recessively inherited syndromic deafness. MAP3K1 phosphorylates serine and threonine 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. Our single-cell transcriptome data of mouse cochlea mRNA show expression of Map3k1 and its signaling partners in several inner ear cell types suggesting a requirement of wild-type MAP3K1 for normal hearing. In contrast to dominant variants of MAP3K1 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 MAP3K1, consistent with the limited phenotype of nonsyndromic deafness. [ABSTRACT FROM AUTHOR]
- Subjects :
- SEX differentiation disorders
DEAFNESS
GENE expression
INNER ear
HEARING disorders
Subjects
Details
- Language :
- English
- ISSN :
- 20734425
- Volume :
- 15
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- Genes
- Publication Type :
- Academic Journal
- Accession number :
- 178689323
- Full Text :
- https://doi.org/10.3390/genes15070845