Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice

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dc.contributor.authorBademci, Guney
dc.contributor.authorLachgar-Ruiz, Maria
dc.contributor.authorDeokar, Mangesh
dc.contributor.authorZafeer, Mohammad Faraz
dc.contributor.authorAbad, Clemer
dc.contributor.authorBaylan, Muzeyyen Yildirim
dc.contributor.authorIngham, Neil J.
dc.date.accessioned2024-04-24T16:24:14Z
dc.date.available2024-04-24T16:24:14Z
dc.date.issued2022
dc.departmentDicle Üniversitesien_US
dc.description.abstractDiscovery of deafness genes and elucidating their functions have substantially contributed to our understanding of hearing physiology and its pathologies. Here we report on DNA variants in MINAR2, encoding membrane integral NOTCH2-associated receptor 2, in four families underlying autosomal recessive nonsyndromic deafness. Neurologic evaluation of affected individuals at ages ranging from 4 to 80 y old does not show additional abnormalities. MINAR2 is a recently annotated gene with limited functional understanding. We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419de1CGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL). The c.393G > T variant is shown to disrupt a splice donor site. We show that Minar2 is expressed in the mouse inner ear, with the protein localizing mainly in the hair cells, spiral ganglia, the spiral limbus, and the stria vascularis. Mice with loss of function of the Minar2 protein (Minar2(tm1b/tm1b)) present with rapidly progressive sensorineural HL associated with a reduction in outer hair cell stereocilia in the shortest row and degeneration of hair cells at a later age. We conclude that MINAR2 is essential for hearing in humans and mice and its disruption leads to sensorineural HL. Progressive HL observed in mice and in some affected individuals and as well as relative preservation of hair cells provides an opportunity to interfere with HL using genetic therapies.en_US
dc.description.sponsorshipNIH/National Institute on Deafness [R01DC009645, R01DC012836]; National Institute for Health and Care Research Biomedical Research Centre, King's College London; Royal National Institute for Deaf People; Wellcome Trust; Rajarshi Shahu College of Pharmacy, Malvihir, Buldana, Indiaen_US
dc.description.sponsorshipWe are immensely grateful to all the patients and families participating in this study. This study was supported by R01DC009645 and R01DC012836 from the NIH/National Institute on Deafness (M.T.), the National Institute for Health and Care Research Biomedical Research Centre, King's College London (K.P.S.), and the Royal National Institute for Deaf People (K.P.S.). This research was funded in part by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We thank the Wellcome Sanger Institute Mouse Genetics Project for generating and providing the Minar2 mouse mutant. M.D. and G.H. would also like to express sincere gratitude for all the support provided by Dr. S. P. Jain, Principal, Rajarshi Shahu College of Pharmacy, Malvihir, Buldana, India.en_US
dc.identifier.doi10.1073/pnas.2204084119
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.issue26en_US
dc.identifier.pmid35727972en_US
dc.identifier.scopus2-s2.0-85132292951en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1073/pnas.2204084119
dc.identifier.urihttps://hdl.handle.net/11468/16594
dc.identifier.volume119en_US
dc.identifier.wosWOS:000854979800005
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoenen_US
dc.publisherNatl Acad Sciencesen_US
dc.relation.ispartofProceedings of The National Academy of Sciences of The United States of Americaen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectAutosomal Recessiveen_US
dc.subjectDeafnessen_US
dc.subjectHearing Lossen_US
dc.subjectMinar2en_US
dc.subjectNotch2en_US
dc.titleMutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and miceen_US
dc.typeArticleen_US

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