{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T22:29:30Z","timestamp":1780525770664,"version":"3.54.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"the Foundation of Shanghai Ji Ai Genetics and IVF Institute","award":["JA-2018-01"],"award-info":[{"award-number":["JA-2018-01"]}]},{"name":"the Foundation of Shanghai Ji Ai Genetics and IVF Institute","award":["20QC1400100"],"award-info":[{"award-number":["20QC1400100"]}]},{"name":"the Excellent Doctors-Excellent Clinical Researchers Program","award":["SYB202008"],"award-info":[{"award-number":["SYB202008"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21ZR1411800"],"award-info":[{"award-number":["21ZR1411800"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["20204Y0071, 20194Y0036"],"award-info":[{"award-number":["20204Y0071, 20194Y0036"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101753, 81900148, 81802903"],"award-info":[{"award-number":["82101753, 81900148, 81802903"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Non-syndromic sensorineural hearing loss (NSHL) is a group of genetically heterogeneous conditions with broad phenotypic heterogeneity. There is, at present, no curative treatment for genetic hearing loss (HL). Early molecular diagnosis of progressive disorders and elucidation of the causes and pathomechanisms are essential for developing therapeutic strategies. Here, we identified a novel rare frameshift variant of LMX1A (c.915dup), which resulted in the C-terminal-altered and -truncated LMX1A (p.Val306Cysfs*32). This C-terminal frameshift mutation co-segregated with autosomal dominant (AD) NSHL in a four-generation Chinese family, suggesting that the LMX1A non-missense mutation is also contributed to ADNSHL. In this family, the affected individuals exhibited the variable auditory phenotypes ranging from profound congenital deafness at birth or to mild\/moderate HL in adulthood. We also found that the embryonic cells carrying with the heterozygous variant significantly expressed several upregulated HL-associated genes at transcriptional level. In vitro splicing assay suggested that the LMX1A mRNA with c.915dup did not cause nonsense-mediated decay and was translated into a truncated LMX1A. In addition, electrophoresis mobility shift assay and luciferase assays have shown that the highly conserved C-terminal domain (amino acid 306\u2013382) of the LMX1A was required for regulating the protein\u2013DNA interaction and transactivation in vitro. Furthermore, apoptosis assays suggested that the C-terminal domain of the LMX1A was important for mediating apoptosis in the cochlear hair cells. Our work provided the multiline of the evidence to support that non-missense mutation of LMX1A leads to ADNSHL and the C-terminal domain of LMX1A is important for mediating transcriptional activity and associated with promoting apoptosis in the cells.<\/jats:p>","DOI":"10.1093\/hmg\/ddac301","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T22:52:43Z","timestamp":1670971963000},"page":"1348-1360","source":"Crossref","is-referenced-by-count":5,"title":["A novel frameshift variant of<i>LMX1A<\/i>that leads to autosomal dominant non-syndromic sensorineural hearing loss: functional characterization of the C-terminal domain in LMX1A"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5720-5109","authenticated-orcid":false,"given":"Min","family":"Xiao","sequence":"first","affiliation":[{"name":"The Obstetrics and Gynecology Hospital of Fudan University Shanghai Ji Ai Genetics and IVF Institute, , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University School of Medicine Department of Pancreatic Surgery, Shanghai General Hospital, , Shanghai 200080 , China"},{"name":"Shanghai Jiao Tong University School of Medicine Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, , Shanghai 200080 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Hsiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Shanghai Jingzhou Medical Laboratory Corporation Company Limited , Shanghai 201321 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanhe","family":"Yu","sequence":"additional","affiliation":[{"name":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbi","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Obstetrics and Gynecology Hospital of Fudan University Shanghai Ji Ai Genetics and IVF Institute, , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Xi","sequence":"additional","affiliation":[{"name":"The Obstetrics and Gynecology Hospital of Fudan University Shanghai Ji Ai Genetics and IVF Institute, , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Dou","sequence":"additional","affiliation":[{"name":"Shanghai Jingzhou Medical Laboratory Corporation Company Limited , Shanghai 201321 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxi","family":"Sun","sequence":"additional","affiliation":[{"name":"The Obstetrics and Gynecology Hospital of Fudan University Shanghai Ji Ai Genetics and IVF Institute, , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caixia","family":"Lei","sequence":"additional","affiliation":[{"name":"The Obstetrics and Gynecology Hospital of Fudan University Shanghai Ji Ai Genetics and IVF Institute, , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5769-9583","authenticated-orcid":false,"given":"Huiqian","family":"Yu","sequence":"additional","affiliation":[{"name":"Fudan University Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, , Shanghai 200031 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"key":"2023040610555314400_","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.otc.2015.06.005","article-title":"Genetics of hearing loss--nonsyndromic","volume":"48","author":"Chang","year":"2015","journal-title":"Otolaryngol. Clin. North Am."},{"key":"2023040610555314400_","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.heares.2019.01.003","article-title":"Hereditary hearing loss; about the known and the unknown","volume":"376","author":"Kremer","year":"2019","journal-title":"Hearing Res."},{"key":"2023040610555314400_","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00439-018-1880-5","article-title":"Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction","volume":"137","author":"Wesdorp","year":"2018","journal-title":"Hum. Genet."},{"key":"2023040610555314400_","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1002\/humu.24095","article-title":"Novel genotype-phenotype correlation of functionally characterized LMX1A variants linked to sensorineural hearing loss","volume":"41","author":"Lee","year":"2020","journal-title":"Hum. 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