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To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in\n                    <jats:italic>PCDHA9<\/jats:italic>\n                    in three unrelated patients. We generated\n                    <jats:italic>Pcdh\u03b19<\/jats:italic>\n                    mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural\/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that\n                    <jats:italic>Pcdha9<\/jats:italic>\n                    mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-\u03b11 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present\n                    <jats:italic>PCDHA9<\/jats:italic>\n                    as a potential ALS gene and provide insights into its pathogenesis.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-46333-5","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T10:03:30Z","timestamp":1710151410000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["PCDHA9 as a candidate gene for amyotrophic lateral sclerosis"],"prefix":"10.1038","volume":"15","author":[{"given":"Jie","family":"Zhong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8784-1002","authenticated-orcid":false,"given":"Chaodong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7970-8332","authenticated-orcid":false,"given":"Dan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2613-7956","authenticated-orcid":false,"given":"Xiaoli","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanzhen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xusheng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3577-9774","authenticated-orcid":false,"given":"Chun","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0872-8189","authenticated-orcid":false,"given":"Yaqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruojie","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu-Ying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qibin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5989-5377","authenticated-orcid":false,"given":"Mingbang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoli","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1633-4470","authenticated-orcid":false,"given":"Shabbir Khan","family":"Afridi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8956-7238","authenticated-orcid":false,"given":"Wenhao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanjun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7908-235X","authenticated-orcid":false,"given":"Yanming","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4809-2851","authenticated-orcid":false,"given":"Zhiheng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,11]]},"reference":[{"key":"46333_CR1","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/bs.pmch.2018.12.001","volume":"58","author":"K Valko","year":"2019","unstructured":"Valko, K. & Ciesla, L. 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