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POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

Lookup NU author(s): Professor Giorgio TascaORCiD


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The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by wholeexome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1S201F displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1S201F and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1S201F in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1S191F) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases.

Publication metadata

Author(s): Schindler RFR, Scotton C, Zhang J, Passarelli C, Ortiz-Bonnin B, Simrick S, Schwerte T, Poon K-L, Fang M, Rinne S, Froese A, Nikolaev VO, Grunert C, Muller T, Tasca G, Sarathchandra P, Drago F, Dallapiccola B, Rapezzi C, Arbustini E, Romana Di Raimo F, Neri M, Selvatici R, Gualandi F, Fattori F, Pietrangelo A, Li W, Jiang H, Xu X, Bertini E, Decher N, Wang J, Brand T, Ferlini A

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2016

Volume: 126

Issue: 1

Pages: 239-253

Print publication date: 04/01/2016

Online publication date: 07/12/2015

Acceptance date: 01/01/1900

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI79562

PubMed id: 26642364


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