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Bi-allelic pathogenic variants in\n                    <jats:italic>PPP1R21<\/jats:italic>\n                    were linked to a neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) with pediatric onset. Functional studies unraveled impaired vesicular transport as being part of PPP1R21-related pathomechanism. To decipher further the pathophysiological processes leading to the clinical manifestation of NEDHFBA, we investigated the proteomic signature of fibroblasts derived from the first NEDHFBA patient harboring a splice-site mutation in\n                    <jats:italic>PPP1R21<\/jats:italic>\n                    and presenting with a milder phenotype. Proteomic findings and further functional studies demonstrate a profound activation of the ubiquitin\u2013proteasome system with presence of protein aggregates and impact on cellular fitness and moreover suggest a cross-link between activation of the proteolytic system and cytoskeletal architecture (including filopodia) as exemplified on paradigmatic proteins including actin, thus extending the pathophysiological spectrum of the disease. In addition, the proteomic signature of\n                    <jats:italic>PPP1R21<\/jats:italic>\n                    -mutant fibroblasts displayed a dysregulation of a variety of proteins of neurological relevance. This includes increase proteins which might act toward antagonization of cellular stress burden in terms of pro-survival, a molecular finding which might accord with the presentation of a milder phenotype of our NEDHFBA patient.\n                  <\/jats:p>","DOI":"10.1007\/s12035-023-03219-9","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T03:30:31Z","timestamp":1674531031000},"page":"2602-2618","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A  Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function"],"prefix":"10.1007","volume":"60","author":[{"given":"Andreas","family":"Hentschel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai","family":"Kohlschmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Gro\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Sickmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Schara-Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"F\u00f6rster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"T\u00f6pf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Christiansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Vorgerd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Polavarapu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Preusse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Hannappel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Sch\u00e4nzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika","family":"Gr\u00fcneboom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gangfu\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2050-2115","authenticated-orcid":false,"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"3219_CR1","doi-asserted-by":"publisher","first-page":"e1006543","DOI":"10.1371\/journal.pgen.1006543","volume":"13","author":"N Peel","year":"2017","unstructured":"Peel N, Iyer J, Naik A et al (2017) Protein phosphatase 1 down regulates ZYG-1 levels to limit centriole duplication. 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Approval was granted by the Ethics Committee of University Duisburg-Essen (04.02.2020 10\u20139011-BO).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Written informed consent was obtained from the parents.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"N\/A.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"Seven of the authors of this publication are members of the European Reference Network for Neuromuscular Diseases-Project ID N\u00b0 870177. Three authors of this study are part of the Center for Translational Neuro- and Behavioral Sciences (C-NTBS). The other authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}