{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:34:26Z","timestamp":1787592866949,"version":"build-2736575974"},"reference-count":64,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIDCD","award":["DIR DC000088"],"award-info":[{"award-number":["DIR DC000088"]}]},{"name":"NIDCD","award":["DC000039"],"award-info":[{"award-number":["DC000039"]}]},{"name":"NIDCD","award":["ZIC DC000086"],"award-info":[{"award-number":["ZIC DC000086"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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&gt;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.<\/jats:p>","DOI":"10.3390\/genes15070845","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T03:42:30Z","timestamp":1719546150000},"page":"845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1-Deficient Mice"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7788-8755","authenticated-orcid":false,"given":"Rabia","family":"Faridi","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizwan","family":"Yousaf","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9064-0762","authenticated-orcid":false,"given":"Sayaka","family":"Inagaki","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafal","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Auditory Development and Restoration Program, National Institute on 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0035-5341","authenticated-orcid":false,"given":"Elizabeth","family":"Wilson","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanveer","family":"Qaiser","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Sector G-8\/3, Ravi Road, Islamabad 44000, 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