{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T23:33:23Z","timestamp":1791502403421,"version":"4.3.4"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AI Health Innovation Cluster","award":["AIH23"],"award-info":[{"award-number":["AIH23"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["YI 209\/1-1, AOBJ 680080"],"award-info":[{"award-number":["YI 209\/1-1, AOBJ 680080"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of cortical and spinal motor neurons. Mendelian germline mutations often cause familial ALS (fALS) but only approximately 10% of sporadic ALS cases (sALS).<\/jats:p>\n                  <jats:p>We leveraged DNA and single-cell RNA sequencing data from autopsy tissue to explore the presence of somatic mosaic variants in sALS cases.<\/jats:p>\n                  <jats:p>Deep targeted panel sequencing of known ALS disease genes in motor cortex tissue revealed an enrichment of low allele frequency variants in sALS, but not in fALS with an identified monogenic cause. In silico analysis predicted increased pathogenicity of mosaic mutations in various known ALS mutational hot-spots. In particular, we identified the somatic FUS variant p.E516X, located in an established hotspot for germline ALS mutations, which leads to nucleo-cytoplasmic mislocalization and aggregation typical for ALS FUS pathology. Additionally, we performed somatic variant calling on single-cell RNA-sequencing data from sALS tissue and revealed a specific accumulation of somatic variants in excitatory neurons, reinforcing a neuron-autonomous disease initiation.<\/jats:p>\n                  <jats:p>Collectively, this study indicates that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to sALS development.<\/jats:p>","DOI":"10.1093\/brain\/awaf460","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T13:12:35Z","timestamp":1765372355000},"page":"778-784","source":"Crossref","is-referenced-by-count":5,"title":["Somatic gene mutations in the motor cortex of patients with sporadic amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"149","author":[{"given":"\u00d3scar","family":"Gonz\u00e1lez-Velasco","sequence":"first","affiliation":[{"name":"Department of Applied Bioinformatics, German Cancer Research Center (DKFZ) , Heidelberg 69120 ,","place":["Germany"]},{"name":"Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University , Mannheim 68167 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Parlato","sequence":"additional","affiliation":[{"name":"Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University , Mannheim 68167 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcstem","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University , Mannheim 68167 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Decker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University , Ulm 89081 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Menge","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University , Ulm 89081 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Freischmidt","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University , Ulm 89081 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Utah , Salt Lake City, UT 84111 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikshitha","family":"Tulasi","sequence":"additional","affiliation":[{"name":"Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University , Mannheim 68167 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1535-3146","authenticated-orcid":false,"given":"David","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University , Ulm 89081 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0094-5429","authenticated-orcid":false,"given":"Peter M","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Neurosciences, Ume\u00e5 University , Ume\u00e5 90187 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-6026","authenticated-orcid":false,"given":"Karin M E","family":"Forsberg","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Neurosciences, Ume\u00e5 University , Ume\u00e5 90187 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes C M","family":"Schlachetzki","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California , San Diego, La Jolla, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Brors","sequence":"additional","affiliation":[{"name":"Department of Applied Bioinformatics, German Cancer Research Center (DKFZ) , Heidelberg 69120 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8646-2817","authenticated-orcid":false,"given":"Lena","family":"Voith von Voithenberg","sequence":"additional","affiliation":[{"name":"Department of Applied Bioinformatics, German Cancer Research Center (DKFZ) , Heidelberg 69120 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen H","family":"Weishaupt","sequence":"additional","affiliation":[{"name":"Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University , Mannheim 68167 ,","place":["Germany"]},{"name":"Department of Neurology, Ulm University , Ulm 89081 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"2026030512071107400_awaf460-B1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.nrleng.2015.12.019","article-title":"Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis","volume":"34","author":"Riancho","year":"2019","journal-title":"Neurolog\u00eda (Engl Ed)"},{"issue":"1","key":"2026030512071107400_awaf460-B2","first-page":"3","article-title":"Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (review)","volume":"5","author":"Martin","year":"2000","journal-title":"Int J Mol Med"},{"key":"2026030512071107400_awaf460-B3","doi-asserted-by":"crossref","first-page":"e200109","DOI":"10.1212\/NXG.0000000000200109","article-title":"Estimated familial amyotrophic lateral sclerosis proportion: A literature review and meta-analysis","volume":"9","author":"Barberio","year":"2023","journal-title":"Neurol Genet"},{"key":"2026030512071107400_awaf460-B4","doi-asserted-by":"crossref","first-page":"3117.e1","DOI":"10.1016\/j.neurobiolaging.2015.08.005","article-title":"De novo FUS mutations are the most frequent genetic cause in early-onset German 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