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Here, proteomic profiling of skin fibroblasts from severe (SMA I), intermediate (SMA II), and mild (SMA III) patients, alongside age-matched controls, was conducted using SWATH mass spectrometry analysis. Differentially expressed proteomic profiles showed limited overlap across each SMA type, and variability was greatest within SMA II fibroblasts, which was not explained by SMN2 copy number. Despite limited proteomic overlap, enriched canonical pathways common to two of three SMA severities with at least one differentially expressed protein from the third included mTOR signalling, regulation of eIF2 and eIF4 signalling, and protein ubiquitination. Network expression clustering analysis identified protein profiles that may discriminate or correlate with SMA severity. From these clusters, the differential expression of PYGB (SMA I), RAB3B (SMA II), and IMP1 and STAT1 (SMA III) was verified by Western blot. All SMA fibroblasts were transfected with an SMN-enhanced construct, but only RAB3B expression in SMA II fibroblasts demonstrated an SMN-dependent response. The diverse proteomic profiles and pathways identified here pave the way for studies to determine their utility as biomarkers for patient stratification or monitoring treatment efficacy and for the identification of severity-specific treatments.<\/jats:p>","DOI":"10.3390\/cells11172624","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T21:05:12Z","timestamp":1661288712000},"page":"2624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Proteome Signatures of Fibroblasts from Patients with Severe, Intermediate and Mild Spinal Muscular Atrophy Show Limited Overlap"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9671-7054","authenticated-orcid":false,"given":"Sharon J.","family":"Brown","sequence":"first","affiliation":[{"name":"School of Pharmacy and Bioengineering (PhaB), Keele University, Keele ST5 5BG, UK"},{"name":"Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1692-2208","authenticated-orcid":false,"given":"Rachel A.","family":"Kline","sequence":"additional","affiliation":[{"name":"The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK"},{"name":"Euan MacDonald Centre, University of Edinburgh, Edinburgh EH16 4SB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia A.","family":"Synowsky","sequence":"additional","affiliation":[{"name":"BSRC Mass Spectrometry and Proteomics Facility, University of St Andrews, St Andrews KY16 9ST, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally L.","family":"Shirran","sequence":"additional","affiliation":[{"name":"BSRC Mass Spectrometry and Proteomics Facility, University of St Andrews, St Andrews KY16 9ST, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Holt","sequence":"additional","affiliation":[{"name":"Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly A.","family":"Sillence","sequence":"additional","affiliation":[{"name":"Bio-Rad Laboratories, Watford WD17 1ET, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-9445","authenticated-orcid":false,"given":"Peter","family":"Claus","sequence":"additional","affiliation":[{"name":"SMATHERIA gGmbH\u2014Non-Profit Biomedical Research Institute, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brunhilde","family":"Wirth","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Institute for Genetics, University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas M.","family":"Wishart","sequence":"additional","affiliation":[{"name":"The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK"},{"name":"Euan MacDonald Centre, University of Edinburgh, Edinburgh EH16 4SB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-869X","authenticated-orcid":false,"given":"Heidi R.","family":"Fuller","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Bioengineering (PhaB), Keele University, Keele ST5 5BG, UK"},{"name":"Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.nmd.2017.11.005","article-title":"Diagnosis and Management of Spinal Muscular Atrophy: Part 1: Recommendations for Diagnosis, Rehabilitation, Orthopedic and Nutritional Care","volume":"28","author":"Mercuri","year":"2018","journal-title":"Neuromuscul. 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