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dc.contributor.authorYousaf, R.
dc.contributor.authorAhmed, Z.M.
dc.contributor.authorGiese, A.P.J.
dc.date.accessioned2019-06-05T18:28:21Z
dc.date.available2019-06-05T18:28:21Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85045074764&doi=10.1172%2fJCI97350&partnerID=40&md5=1794c7d17eb6876784a3bd07d8bf8e3b
dc.identifier.urihttp://hdl.handle.net/10713/9481
dc.description.abstractA modifier variant can abrogate the risk of a monogenic disorder. DFNM1 is a locus on chromosome 1 encoding a dominant suppressor of human DFNB26 recessive, profound deafness. Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin homology domain of GRB2-associated binding protein 1 (GAB1), an essential scaffold in the MET proto-oncogene, receptor tyrosine kinase/HGF (MET/HGF) pathway. A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1-associated deafness. In zebrafish, human METTL13 mRNA harboring the modifier allele rescued the GAB1-associated morphant phenotype. In mice, GAB1 and METTL13 colocalized in auditory sensory neurons, and METTL13 coimmunoprecipitated with GAB1 and SPRY2, indicating at least a tripartite complex. Expression of MET-signaling genes in human lymphoblastoid cells of individuals homozygous for p.Gly116Glu GAB1 revealed dysregulation of HGF, MET, SHP2, and SPRY2, all of which have reported variants associated with deafness. However, SPRY2 was not dysregulated in normal-hearing humans homozygous for both the GAB1 DFNB26 deafness variant and the dominant METTL13 deafness suppressor, indicating a plausible mechanism of suppression. Identification of METTL13-based modification of MET signaling offers a potential therapeutic strategy for a wide range of associated hearing disorders. Furthermore, MET signaling is essential for diverse functions in many tissues including the inner ear. Therefore, identification of the modifier of MET signaling is likely to have broad clinical implications. Copyright 2018 American Society for Clinical Investigation. All rights reserved.en_US
dc.description.sponsorshipThis research was supported in part by the Intramural Research Program of the NIH, NIDCD (DC000039-20, to TBF), by an Action on Hearing Loss grant, and by NIH, NIDCD research grants R56DC011803 (to Saima Riazud-din) and R01DC012564 to (ZMA).en_US
dc.description.urihttps://dx.doi.org/10.1172/JCI97350en_US
dc.language.isoen-USen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.ispartofJournal of Clinical Investigation
dc.subject.meshDeafness--geneticsen_US
dc.titleModifier variant of METTL13 suppresses human GAB1-associated profound deafnessen_US
dc.typeArticleen_US
dc.identifier.doi10.1172/JCI97350


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