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Mislocalization of TDP\u201043 and formation of insoluble TDP\u201043\u2010positive neuronal cytoplasmic inclusions is the hallmark pathology in &gt;95% of ALS patients. Neuropathological examination of the single case for which CNS tissue was available indicated typical TDP\u201043 pathology within lower motor neurons, but classical TDP\u201043\u2010positive inclusions were absent from motor cortex. The mutated allele is transcribed and translated in patient fibroblasts and motor cortex tissue, but overall TDP\u201043 protein expression is reduced compared to wild\u2010type controls. Despite absence of TDP\u201043\u2010positive inclusions we confirmed deficient TDP\u201043 splicing function within motor cortex tissue. Furthermore, urea fractionation and mass spectrometry of motor cortex tissue carrying the mutation revealed atypical TDP\u201043 protein species but not typical C\u2010terminal fragments. We conclude that the p.Y374X mutation underpins a monogenic, fully penetrant form of ALS. Reduced expression of TDP\u201043 combined with atypical TDP\u201043 protein species and absent C\u2010terminal fragments extends the molecular phenotypes associated with TDP\u201043 mutations and with ALS more broadly. Future work will need to include the findings from this pedigree in dissecting the mechanisms of TDP\u201043\u2010mediated toxicity.<\/jats:p>","DOI":"10.1111\/bpa.13104","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:18:40Z","timestamp":1658708320000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Atypical<scp>TDP<\/scp>\u201043 protein expression in an<scp>ALS<\/scp>pedigree carrying a p.<scp>Y374X<\/scp>truncation mutation in<i>TARDBP<\/i>"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-8689","authenticated-orcid":false,"given":"Johnathan","family":"Cooper\u2010Knock","sequence":"first","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN) University of Sheffield Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas H.","family":"Julian","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN) University of Sheffield Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5905-3826","authenticated-orcid":false,"given":"Emily","family":"Feneberg","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK"},{"name":"Neurology Department, Klinikum Rechts der Isar Technical University of Munich Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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