{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:22:23Z","timestamp":1790511743859,"version":"4.1.0"},"reference-count":35,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T00:00:00Z","timestamp":1635120000000},"content-version":"vor","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["NRF-2017M3A9B4061409"],"award-info":[{"award-number":["NRF-2017M3A9B4061409"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2020M3H4A1A03084600"],"award-info":[{"award-number":["2020M3H4A1A03084600"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2021R1I1A2044117"],"award-info":[{"award-number":["2021R1I1A2044117"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ministry of Health and Welfare","award":["HI20C0039"],"award-info":[{"award-number":["HI20C0039"]}]},{"DOI":"10.13039\/501100007603","name":"Korea Food and Drug Administration","doi-asserted-by":"crossref","award":["14182KFDA978"],"award-info":[{"award-number":["14182KFDA978"]}],"id":[{"id":"10.13039\/501100007603","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007603","name":"Korea Food and Drug Administration","doi-asserted-by":"crossref","award":["21173MFDS562"],"award-info":[{"award-number":["21173MFDS562"]}],"id":[{"id":"10.13039\/501100007603","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The microrchidia (MORC)-family CW-type zinc finger 2 (MORC2) gene is related to DNA repair, adipogenesis and epigenetic silencing via the human silencing hub (HUSH) complex. MORC2 missense mutation is known to cause peripheral neuropathy of Charcot-Marie-Tooth disease type 2 Z (CMT2Z). However, there have been reports of peripheral and central neuropathy in patients, and the disease has been co-categorized with developmental delay, impaired growth, dysmorphic facies and axonal neuropathy (DIGFAN). The etiology of MORC2 mutation-mediated neuropathy remains uncertain. Here, we established and analyzed Morc2a p.S87L mutant mice. Morc2a p.S87L mice displayed the clinical symptoms expected in human CMT2Z patients, such as axonal neuropathy and skeletal muscle weakness. Notably, we observed severe central neuropathy with cerebella ataxia, cognition disorder and motor neuron degeneration in the spinal cord, and this seemed to be evidence of DIGFAN. Morc2a p.S87L mice exhibited an accumulation of DNA damage in neuronal cells, followed by p53\/cytochrome c\/caspase 9\/caspase 3-mediated apoptosis. This study presents a new mouse model of CMT2Z and DIGFAN with a Morc2a p.S87L mutation. We suggest that neuronal apoptosis is a possible target for therapeutic approach in MORC2 missense mutation.<\/jats:p>\n                  <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/dmm.049123","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T13:20:09Z","timestamp":1635168009000},"source":"Crossref","is-referenced-by-count":14,"title":["<i>Morc2a<\/i>\n                    p.S87L mutant mice develop peripheral and central neuropathies associated with neuronal DNA damage and apoptosis"],"prefix":"10.1242","volume":"14","author":[{"given":"Geon Seong","family":"Lee","sequence":"first","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6291-3727","authenticated-orcid":false,"given":"Geon","family":"Kwak","sequence":"additional","affiliation":[{"name":"Department of Neurology, Sungkyunkwan University School of Medicine, 81 Irwonr-ro, Gangnam, Seoul 06351, South Korea"},{"name":"Department of Health Science and Technology, SAIHST, Sungkyunkwan University School of Medicine, 81 Irwonr-ro, Gangnam, Seoul 06351, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6614-5972","authenticated-orcid":false,"given":"Ji Hyun","family":"Bae","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Pil","family":"Han","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Hyun","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Neurology, Sungkyunkwan University School of Medicine, 81 Irwonr-ro, Gangnam, Seoul 06351, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Hyeon","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumin","family":"Song","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gap-Don","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Sub","family":"Park","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5459-1772","authenticated-orcid":false,"given":"Yang Kyu","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, 120 Nueungdong-ro, Gwangjin, Seoul 05029, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5459-1772","authenticated-orcid":false,"given":"Byung-Ok","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Sungkyunkwan University School of Medicine, 81 Irwonr-ro, Gangnam, Seoul 06351, South Korea"},{"name":"Department of Health Science and Technology, SAIHST, Sungkyunkwan University School of Medicine, 81 Irwonr-ro, Gangnam, Seoul 06351, South Korea"},{"name":"Stem Cell and Regenerative Medicine Institute, Samgsung Medical Center, Seoul 06351, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9491-5740","authenticated-orcid":false,"given":"Su Cheong","family":"Yeom","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea"},{"name":"WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak-ro, Gwanank, Seoul 08826, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,10,25]]},"reference":[{"key":"2021102517195991300_DMM049123C1","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1002\/ana.24575","article-title":"MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs","volume":"79","author":"Albulym","year":"2016","journal-title":"Ann. Neurol."},{"key":"2021102517195991300_DMM049123C2","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1111\/ene.13360","article-title":"Clinical and mutational spectrum of Charcot\u2013Marie\u2013Tooth disease type 2Z caused by MORC2 variants in Japan","volume":"24","author":"Ando","year":"2017","journal-title":"Eur. J. Neurol."},{"key":"2021102517195991300_DMM049123C3","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/s41467-018-03045-x","article-title":"Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms","volume":"9","author":"Douse","year":"2018","journal-title":"Nat. Commun."},{"key":"2021102517195991300_DMM049123C4","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1212\/WNL.94.15_supplement.2856","article-title":"Respiratory insufficiency as a feature of MORC2 gene-related Charcot-Marie-Tooth disease type 2: a case report (2856)","volume":"94","author":"Fenton","year":"2020","journal-title":"Neurology"},{"key":"2021102517195991300_DMM049123C5","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.ajhg.2020.06.013","article-title":"De novo variants in the ATPase module of MORC2 cause a neurodevelopmental disorder with growth retardation and variable craniofacial dysmorphism","volume":"107","author":"Guillen Sacoto","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"2021102517195991300_DMM049123C6","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1093\/brain\/awy104","article-title":"Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy","volume":"141","author":"Higuchi","year":"2018","journal-title":"Brain"},{"key":"2021102517195991300_DMM049123C7","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3389\/fnsyn.2018.00006","article-title":"Purkinje cell signaling deficits in animal models of ataxia","volume":"10","author":"Hoxha","year":"2018","journal-title":"Front. Synaptic Neurosci."},{"key":"2021102517195991300_DMM049123C8","doi-asserted-by":"publisher","first-page":"e40","DOI":"10.1093\/brain\/aww082","article-title":"Clinico-genetics in Korean Charcot-Marie-Tooth disease type 2Z with MORC2 mutations","volume":"139","author":"Hyun","year":"2016","journal-title":"Brain"},{"key":"2021102517195991300_DMM049123C9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0037-x","article-title":"Multiple sgRNAs with overlapping sequences enhance CRISPR\/Cas9-mediated knock-in efficiency","volume":"50","author":"Jang","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"2021102517195991300_DMM049123C10","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/1750-1172-2-25","article-title":"Central core disease","volume":"2","author":"Jungbluth","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"2021102517195991300_DMM049123C11","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1017\/S1355617719001188","article-title":"Evidence for cognitive deficits in X-linked Charcot-Marie-Tooth disease","volume":"26","author":"Kasselimis","year":"2020","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"2021102517195991300_DMM049123C12","doi-asserted-by":"publisher","first-page":"e0209628","DOI":"10.1371\/journal.pone.0209628","article-title":"Physical activity of children and adolescents with Charcot-Marie-Tooth neuropathies: a cross-sectional case-controlled study","volume":"14","author":"Kennedy","year":"2019","journal-title":"PLoS ONE"},{"key":"2021102517195991300_DMM049123C13","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s12929-015-0154-y","article-title":"Overexpression of mutant HSP27 causes axonal neuropathy in mice","volume":"22","author":"Lee","year":"2015","journal-title":"J. Biomed. Sci."},{"key":"2021102517195991300_DMM049123C14","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1016\/j.celrep.2012.11.018","article-title":"MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response","volume":"2","author":"Li","year":"2012","journal-title":"Cell Rep."},{"key":"2021102517195991300_DMM049123C15","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1586\/14737175.2015.1017471","article-title":"Therapeutic options in Charcot-Marie-Tooth diseases","volume":"15","author":"Mathis","year":"2015","journal-title":"Expert Rev. Neurother."},{"key":"2021102517195991300_DMM049123C16","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.pmr.2012.06.011","article-title":"Clinical approach to the diagnostic evaluation of hereditary and acquired neuromuscular diseases","volume":"23","author":"McDonald","year":"2012","journal-title":"Phys. Med. Rehabil. Clin. N. Am."},{"key":"2021102517195991300_DMM049123C17","doi-asserted-by":"publisher","first-page":"55523","DOI":"10.3791\/55523","article-title":"Assessment of spontaneous alternation, novel object recognition and limb clasping in transgenic mouse models of amyloid-\u03b2 and Tau neuropathology","author":"Miedel","year":"2017","journal-title":"J. Vis. Exp."},{"key":"2021102517195991300_DMM049123C18","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1093\/dnares\/5.6.355","article-title":"Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro","volume":"5","author":"Nagase","year":"1998","journal-title":"DNA Res."},{"key":"2021102517195991300_DMM049123C19","doi-asserted-by":"publisher","first-page":"59","DOI":"10.3892\/ijo.2018.4333","article-title":"MORC2, a novel oncogene, is upregulated in liver cancer and contributes to proliferation, metastasis and chemoresistance","volume":"53","author":"Pan","year":"2018","journal-title":"Int. J. Oncol."},{"key":"2021102517195991300_DMM049123C20","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.tibs.2003.09.007","article-title":"The CW domain, a structural module shared amongst vertebrates, vertebrate-infecting parasites and higher plants","volume":"28","author":"Perry","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"2021102517195991300_DMM049123C21","doi-asserted-by":"publisher","first-page":"795","DOI":"10.3389\/fneur.2020.00795","article-title":"Brain plasticity in Charcot-Marie-Tooth Type 1A patients? A combined structural and diffusion MRI study","volume":"11","author":"Pontillo","year":"2020","journal-title":"Front. Neurol."},{"key":"2021102517195991300_DMM049123C22","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/j.bbamcr.2013.11.012","article-title":"Cytosolic functions of MORC2 in lipogenesis and adipogenesis","volume":"1843","author":"S\u00e1nchez-Solana","year":"2014","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"2021102517195991300_DMM049123C23","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1093\/hmg\/ddz006","article-title":"Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations","volume":"28","author":"Sancho","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"2021102517195991300_DMM049123C24","doi-asserted-by":"publisher","first-page":"9474","DOI":"10.1073\/pnas.0401702101","article-title":"Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency","volume":"101","author":"Sausbier","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021102517195991300_DMM049123C25","doi-asserted-by":"publisher","first-page":"e70","DOI":"10.1093\/brain\/aww252","article-title":"MORC2 mutation causes severe spinal muscular atrophy-phenotype, cerebellar atrophy, and diaphragmatic paralysis","volume":"139","author":"Schottmann","year":"2016","journal-title":"Brain"},{"key":"2021102517195991300_DMM049123C26","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1093\/brain\/awv311","article-title":"Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease","volume":"139","author":"Sevilla","year":"2016","journal-title":"Brain"},{"key":"2021102517195991300_DMM049123C27","doi-asserted-by":"publisher","first-page":"e1007175","DOI":"10.1371\/journal.pgen.1007175","article-title":"MORC2B is essential for meiotic progression and fertility","volume":"14","author":"Shi","year":"2018","journal-title":"PLoS Genet."},{"key":"2021102517195991300_DMM049123C28","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/978-1-59745-060-7_19","article-title":"Template DNA-strand co-segregation and asymmetric cell division in skeletal muscle stem cells","volume":"482","author":"Shinin","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"2021102517195991300_DMM049123C29","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.jns.2014.10.013","article-title":"Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update","volume":"347","author":"Tazir","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"2021102517195991300_DMM049123C30","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1038\/ng.3878","article-title":"Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2","volume":"49","author":"Tchasovnikarova","year":"2017","journal-title":"Nat. Genet."},{"key":"2021102517195991300_DMM049123C31","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1002\/ar.21119","article-title":"Identification and expression analysis of a novel CW-type zinc finger protein MORC2 in cancer cells","volume":"293","author":"Wang","year":"2010","journal-title":"Anat. Rec."},{"key":"2021102517195991300_DMM049123C32","doi-asserted-by":"publisher","first-page":"e00451","DOI":"10.1002\/brb3.451","article-title":"Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene?","volume":"6","author":"Werheid","year":"2016","journal-title":"Brain Behav."},{"key":"2021102517195991300_DMM049123C33","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1080\/15548627.2019.1659609","article-title":"Stabilization of MORC2 by estrogen and antiestrogens through GPER1- PRKACA-CMA pathway contributes to estrogen-induced proliferation and endocrine resistance of breast cancer cells","volume":"16","author":"Yang","year":"2020","journal-title":"Autophagy"},{"key":"2021102517195991300_DMM049123C34","doi-asserted-by":"publisher","first-page":"e34","DOI":"10.1093\/brain\/awx083","article-title":"De novo p.T362R mutation in MORC2 causes early onset cerebellar ataxia, axonal polyneuropathy and nocturnal hypoventilation","volume":"140","author":"Zanni","year":"2017","journal-title":"Brain"},{"key":"2021102517195991300_DMM049123C35","doi-asserted-by":"publisher","first-page":"5780","DOI":"10.1158\/0008-5472.CAN-17-1394","article-title":"Cancer-associated MORC2-mutant M276I regulates an hnRNPM-mediated CD44 splicing switch to promote invasion and metastasis in triple-negative breast cancer","volume":"78","author":"Zhang","year":"2018","journal-title":"Cancer Res."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049123\/2110340\/dmm049123.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049123\/2110340\/dmm049123.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T15:39:16Z","timestamp":1725982756000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/14\/10\/dmm049123\/272590\/Morc2a-p-S87L-mutant-mice-develop-peripheral-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,1]]},"references-count":35,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2021,10,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.049123","relation":{},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"value":"1754-8403","type":"print"},{"value":"1754-8411","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,1]]},"article-number":"dmm049123"}}