{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:44:54Z","timestamp":1790336694038,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T00:00:00Z","timestamp":1572220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/14\/46\/30911"],"award-info":[{"award-number":["PG\/14\/46\/30911"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/14\/83\/31128"],"award-info":[{"award-number":["PG\/14\/83\/31128"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013995","name":"Sanofi Genzyme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013995","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013780","name":"Limb Girdle Muscular Dystrophy 2i Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011724","name":"Muscular Dystrophy UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011724","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The Popeye domain containing 3 (<jats:italic>POPDC3)<\/jats:italic> gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic <jats:italic>POPDC3<\/jats:italic> variants. Five patients carrying <jats:italic>POPDC3<\/jats:italic> variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish <jats:italic>popdc3<\/jats:italic> knockdown model and heterologous expression of the mutant proteins in <jats:italic>Xenopus laevis<\/jats:italic> oocytes to measure TREK\u20101 current.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified homozygous <jats:italic>POPDC3<\/jats:italic> missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy\u2010terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands\u2019 muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U\/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of <jats:italic>popdc3<\/jats:italic> in zebrafish, using 2 different splice\u2010site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in <jats:italic>Xenopus<\/jats:italic> oocytes caused an aberrant modulation of the mechano\u2010gated potassium channel, TREK\u20101.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in <jats:italic>POPDC3<\/jats:italic> are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832\u2013843<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25620","type":"journal-article","created":{"date-parts":[[2019,10,14]],"date-time":"2019-10-14T16:54:12Z","timestamp":1571072052000},"page":"832-843","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["<i>POPDC3<\/i> Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6144-8544","authenticated-orcid":false,"given":"John","family":"Vissing","sequence":"first","affiliation":[{"name":"Copenhagen Neuromuscular Center, Rigshospitalet University of Copenhagen  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Johnson","sequence":"additional","affiliation":[{"name":"John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine Newcastle University and Newcastle Hospitals NHS Foundation 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Neuromusculars, Servei de Neurologia, Hospital de la Santa Creu i Sant Pau de Barcelona and CIBERER, Madrid  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa M.","family":"French","sequence":"additional","affiliation":[{"name":"Developmental Dynamics, Myocardial Function National Heart and Lung Institute, Imperial College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland F.","family":"Schindler","sequence":"additional","affiliation":[{"name":"Developmental Dynamics, Myocardial Function National Heart and Lung Institute, Imperial College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padmini","family":"Sarathchandra","sequence":"additional","affiliation":[{"name":"Heart Science Centre National Heart and Lung Institute, Imperial College London  London United 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