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Clinical presentations and response to pyridostigmine, moreover, highlighted neuromuscular junction (NMJ) involvement. However, NMJ architecture, underlying molecular mechanisms, and potential minimally invasive biomarkers in PURA syndrome remain poorly characterized. This study aimed to profile PURA-related disease using integrated clinical, histological, ultrastructural, transcriptional, and protein analyses of skeletal muscle and blood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Ten genetically confirmed patients underwent detailed phenotyping with emphasis on congenital myasthenic syndrome (CMS)-like features. Quadriceps biopsy from one patient was analyzed by histology, immunohistochemistry, and electron microscopy. Protein profiling of muscle, serum, and extracellular vesicles (EVs) was performed by ELISA and mass spectrometry, with validation by qPCR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In line with the recognized classification of PURA syndrome as a CMS subtype, our patients exhibited hypotonia, ptosis, ocular weakness, and myopathic facies, reflecting impaired neuromuscular transmission. Subtle vesicle accumulation and minor NMJ alterations suggest possible neuromuscular involvement in PURA syndrome. Muscle proteomics showed reduced PURA protein and dysregulation of transcriptional regulation, vesicle transport, extracellular matrix remodeling, and complement activation. qPCR confirmed\n                      <jats:italic>POSTN<\/jats:italic>\n                      and\n                      <jats:italic>PHGDH<\/jats:italic>\n                      upregulation among others. Serum analyses demonstrated elevated TSP4, identifying a promising candidate blood biomarker for\n                      <jats:italic>PURA<\/jats:italic>\n                      -associated NMJ dysfunction. EV proteomics revealed dysregulated immunoglobulins, complement components, and novel candidates including NOTCH2, TARSH, and PON1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Pathogenic\n                      <jats:italic>PURA<\/jats:italic>\n                      variants may impair NMJ structure and vesicle homeostasis, potentially linking molecular and ultrastructural defects with clinical myasthenic features and pyridostigmine responsiveness. Proteomic analysis of skeletal muscle provides initial molecular insights into the consequences of dominant PURA variants in muscle tissue. The identification of TSP4 and extracellular vesicle-associated proteins as potential minimally invasive biomarkers provides a framework for biochemical monitoring of PURA syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-13621-7","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T14:05:19Z","timestamp":1769177119000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring molecular signatures in PURA syndrome using muscle proteomics and serum biomarkers"],"prefix":"10.1007","volume":"273","author":[{"given":"Magdalena","family":"Mroczek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Preusse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hentschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Chro\u015bci\u0144ska-Krawczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Bielak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adela","family":"Sobolewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adela","family":"Della Marina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anisa","family":"Hila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Iyadurai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkatesh Kumar","family":"Chetty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Muhmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Ruck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Hilmar","family":"Goebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Schara-Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Dobelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basant Kumar","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Stenzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2833-0928","authenticated-orcid":false,"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"13621_CR1","unstructured":"Reijnders MRF, Leventer RJ, Lee BH, Baralle D, Selber P, Paciorkowski AR, Hunt D (1993) PURA-related neurodevelopmental disorders. 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