| Title: |
Somatic gene mutations in the motor cortex of patients with sporadic amyotrophic lateral sclerosis |
| Authors: |
González-Velasco, Óscar; Parlato, Rosanna; Yilmaz, Rüstem; Decker, Lorena; Menge, Sonja; Freischmidt, Axel; Yang, Xiaoxu; Tulasi, Nikshitha; Brenner, David; Andersen, Peter M.; Forsberg, Karin M.E.; Schlachetzki, Johannes C.M.; Brors, Benedikt; von Voithenberg, Lena Voith; Weishaupt, Jochen H. |
| Publisher Information: |
Umeå universitet, Neurovetenskaper; Department of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Neurology, Ulm University, Ulm, Germany; Department of Human Genetics, University of Utah, UT, Salt Lake City, United States; Department of Neurosciences, University of California, La Jolla, CA, San Diego, United States; Department of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Neurology, Ulm University, Ulm, Germany |
| Publication Year: |
2026 |
| Collection: |
Umeå University: Publications (DiVA) |
| Subject Terms: |
amyotrophic lateral sclerosis; excitatory neurons; neuronal somatic mosaicism; somatic variants; Neurology; Neurologi; Neurosciences; Neurovetenskaper |
| Description: |
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). We leveraged DNA and single-cell RNA sequencing data from autopsy tissue to explore the presence of somatic mosaic variants in sALS cases. 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. Collectively, this study indicates that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to sALS development. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Brain, 0006-8950, 2026, 149:3, s. 778-784; PMID 41378777; ISI:001681150600001 |
| DOI: |
10.1093/brain/awaf460 |
| Availability: |
http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-251108; https://doi.org/10.1093/brain/awaf460 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.C7F05CA5 |
| Database: |
BASE |