{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T14:08:41Z","timestamp":1786370921880,"version":"build-2736575974"},"reference-count":28,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T00:00:00Z","timestamp":1724803200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Fred Liuzzi Foundation"},{"DOI":"10.13039\/501100001801","name":"University of Western Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001801","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP2002640"],"award-info":[{"award-number":["APP2002640"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP2007769"],"award-info":[{"award-number":["APP2007769"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013465","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["24438"],"award-info":[{"award-number":["24438"]}],"id":[{"id":"10.13039\/100013465","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["779257"],"award-info":[{"award-number":["779257"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,8,14]]},"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Weakness of facial, ocular and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca<jats:sup>2+<\/jats:sup> homeostasis can contribute to disease pathology.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analysed exome and genome sequencing data from four unrelated individuals with congenital myopathy characterised by facial, ocular and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-sequencing (RNA-seq) data of F3-II.1 and performed gene expression outlier analysis in 129 samples.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The four probands had a remarkably similar clinical presentation with prominent facial, ocular and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatigability. Muscle biopsy on light microscopy showed type 1 myofiber predominance and ultrastructural analysis revealed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum.<\/jats:p>\n                  <jats:p>DNA sequencing identified four unique homozygous loss-of-function variants in <jats:italic>JPH1<\/jats:italic>, encoding junctophilin-1 in the four families; one stop-gain (c.354C&gt;A;p.Tyr118*) and three frameshift (c.373delG;p.Asp125Thrfs*30, c.1738delC;p.Leu580Trpfs*16 and c.1510delG;p. Glu504Serfs*3) variants. Muscle RNA-seq showed strong downregulation of <jats:italic>JPH1<\/jats:italic> in the F3 proband.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Junctophilin-1 is critical for the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of <jats:italic>JPH1<\/jats:italic> results in a congenital myopathy with prominent facial, bulbar and ocular involvement.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2024-109970","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T00:35:48Z","timestamp":1724891748000},"page":"992-998","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Loss-of-function variants in <i>JPH1<\/i> cause congenital myopathy with prominent facial and ocular involvement"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3549-558X","authenticated-orcid":false,"given":"Mridul","family":"Johari","sequence":"first","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, Western Australia, Australia"},{"name":"Folkh\u00e4lsan Research Center, Helsinki, Finland"},{"name":"Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Topf","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"}]},{"given":"Chiara","family":"Folland","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Duff","sequence":"additional","affiliation":[{"name":"The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University 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Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Vilchez","sequence":"additional","affiliation":[{"name":"Neuromuscular Research Group, IIS La Fe and CIBERER U763, Hospital Universitari i Polit\u00e8cnic La Fe, Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Cairns","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Queensland Children's Hospital, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Harris","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"}]},{"given":"Chiara","family":"Marini-Bettolo","sequence":"additional","affiliation":[{"name":"The John Walton Muscular 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