{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:56:43Z","timestamp":1788245803503,"version":"build-2803163510"},"reference-count":32,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["CFI\u2010JELF 38412"],"award-info":[{"award-number":["CFI\u2010JELF 38412"]}],"id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FDN\u2010167281"],"award-info":[{"award-number":["FDN\u2010167281"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["309548"],"award-info":[{"award-number":["309548"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013465","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["21466"],"award-info":[{"award-number":["21466"]}],"id":[{"id":"10.13039\/100013465","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007472","name":"University of Kentucky","doi-asserted-by":"publisher","award":["MR\/N025431\/1"],"award-info":[{"award-number":["MR\/N025431\/1"]}],"id":[{"id":"10.13039\/100007472","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["R01 HG009141"],"award-info":[{"award-number":["R01 HG009141"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["UM1 HG008900"],"award-info":[{"award-number":["UM1 HG008900"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recessive variants in <jats:italic>WASHC4<\/jats:italic> are linked to intellectual disability complicated by poor language skills, short stature, and dysmorphic features. The protein encoded by <jats:italic>WASHC4<\/jats:italic> is part of the Wiskott\u2013Aldrich syndrome protein and SCAR homolog family, co\u2010localizes with actin in cells, and promotes Arp2\/3\u2010dependent actin polymerization <jats:italic>in vitro<\/jats:italic>. Functional studies in a zebrafish model suggested that <jats:italic>WASHC4<\/jats:italic> knockdown may also affect skeletal muscles by perturbing protein clearance. However, skeletal muscle involvement has not been reported so far in patients, and precise biochemical studies allowing a deeper understanding of the molecular etiology of the disease are still lacking. Here, we report two siblings with a homozygous <jats:italic>WASHC4<\/jats:italic> variant expanding the clinical spectrum of the disease and provide a phenotypical comparison with cases reported in the literature. Proteomic profiling of fibroblasts of the WASHC4\u2010deficient patient revealed dysregulation of proteins relevant for the maintenance of the neuromuscular axis. Immunostaining on a muscle biopsy derived from the same patient confirmed dysregulation of proteins relevant for proper muscle function, thus highlighting an affliction of muscle cells upon loss of functional WASHC4. The results of histological and coherent anti\u2010Stokes Raman scattering microscopic studies support the concept of a functional role of the WASHC4 protein in humans by altering protein processing and clearance. The proteomic analysis confirmed key molecular players <jats:italic>in vitro<\/jats:italic> and highlighted, for the first time, the involvement of skeletal muscle in patients. \u00a9 2021 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5812","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T06:51:10Z","timestamp":1633330270000},"page":"93-107","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Homozygous <scp><i>WASHC4<\/i><\/scp> variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement"],"prefix":"10.1002","volume":"256","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9975-0092","authenticated-orcid":false,"given":"Andrea","family":"Gangfu\u00df","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro\u2010 and Behavioral Sciences University Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Czech","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Institut f\u00fcr Analytische Wissenschaften \u2013 ISAS \u2013 e.V.  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hentschel","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Institut f\u00fcr Analytische Wissenschaften \u2013 ISAS \u2013 e.V.  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"M\u00fcnchberg","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Institut f\u00fcr Analytische Wissenschaften \u2013 ISAS \u2013 e.V.  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"T\u00f6pf","sequence":"additional","affiliation":[{"name":"The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University and Newcastle Hospitals NHS Foundation Trust  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7669-8239","authenticated-orcid":false,"given":"Emily","family":"O'Heir","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics, Program in Medical and Population Genetics Broad Institute of MIT and Harvard  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders Medical Center \u2013 University of Freiburg, Faculty of Medicine  Freiburg Germany"},{"name":"Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG\u2010CRG), Center for Genomic Regulation Barcelona Institute of Science and Technology (BIST)  Barcelona Spain"},{"name":"Children's Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital; and Brain and Mind Research Institute University of Ottawa  Ottawa Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Stehling","sequence":"additional","affiliation":[{"name":"Children's Hospital, Department of Pneumology University Hospital Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cordula","family":"Kiewert","sequence":"additional","affiliation":[{"name":"Children's Hospital, Department of Endocrinology University Hospital Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Sickmann","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Institut f\u00fcr Analytische Wissenschaften \u2013 ISAS \u2013 e.V.  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