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Here, we investigated whether <jats:italic>SUMO4<\/jats:italic> variants play a role in ALS pathogenesis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Whole-exome or targeted <jats:italic>SUMO4<\/jats:italic> sequencing was done in 222 unrelated European ALS patients. The consequences of the identified initiator codon variant were analyzed at the mRNA, protein and cellular level. <jats:italic>SUMO4<\/jats:italic> expression was quantified in human tissues. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A rare heterozygous <jats:italic>SUMO4<\/jats:italic> variant, i.e., <jats:italic>SUMO4<\/jats:italic>:c.2T&gt;C p.Met1?, was detected in four of 222 (1.8%) ALS patients, significantly more frequently than in two control cohorts (0.3% each). <jats:italic>SUMO4<\/jats:italic> mRNA and protein expression was diminished in whole blood or fibroblasts of a <jats:italic>SUMO4<\/jats:italic> variant carrier versus controls. Pertinent stress factors, i.e., head trauma or cancer (treated by radiochemotherapy), were significantly more frequent in <jats:italic>SUMO4<\/jats:italic> variant carrier versus non-carrier ALS patients. The mean number of SGs per cell was significantly higher in fibroblasts of a <jats:italic>SUMO4<\/jats:italic> variant carrier compared to controls at baseline, upon oxidative stress, and after recovery, and SUMOylation of ALS-associated valosin-containing protein by SUMO4 was decreased. <jats:italic>SUMO4<\/jats:italic> mRNA expression was highest in brain of all human tissues analyzed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our results are consistent with <jats:italic>SUMO4<\/jats:italic> haploinsufficiency as a contributor to ALS pathogenesis impacting SG dynamics and possibly acting in conjunction with environmental oxidative stress-related factors.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00415-022-11126-7","type":"journal-article","created":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T12:03:08Z","timestamp":1651579388000},"page":"4863-4871","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A SUMO4 initiator codon variant in amyotrophic lateral sclerosis reduces SUMO4 expression and alters stress granule dynamics"],"prefix":"10.1007","volume":"269","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6012-8423","authenticated-orcid":false,"given":"Alma","family":"Osmanovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7842-8483","authenticated-orcid":false,"given":"Alisa","family":"F\u00f6rster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maylin","family":"Widjaja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Auber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anibh M.","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Christians","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5537-8543","authenticated-orcid":false,"given":"Frank","family":"Brand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9783-8584","authenticated-orcid":false,"given":"Susanne","family":"Petri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6610-1080","authenticated-orcid":false,"given":"Ruthild G.","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,3]]},"reference":[{"issue":"11","key":"11126_CR1","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1038\/s41583-019-0222-5","volume":"20","author":"B Wolozin","year":"2019","unstructured":"Wolozin B, Ivanov P (2019) Stress granules and neurodegeneration. 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The other authors report no conflict of interest relevant to this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"This study was approved by the Ethics Board of Hannover Medical School (ID # 6269) and was, therefore, performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent was obtained from all individuals before entering the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}