Pinpointing the cause of a familial muscular dystrophy

Muscular dystrophies are congenital disorders that result in weakening and loss of skeletal muscle. Many muscular dystrophy phenotypes are also accompanied by cardiac manifestations, such as cardiomyopathy and cardiac arrhythmias. The plasma membrane-localized, cAMP-binding protein POPDC1 is abundant in striated muscle, and in animal models, mutations in POPDC-encoding genes result in both skeletal and cardiac muscle dysfunction. Despite the strong link to cardiac and skeletal muscle pathology in model organisms, POPDC1 mutations are not associated with human muscular dystrophies. Roland Schindler, Chiara Scotton, Jianguo Zhang, and colleagues at Imperial College London, University of Ferrara, and BGI-Shenzhen have identified a missense mutation in POPDC1 (POPDC1 S191F) in a family with limb-girdle muscular dystrophy (LGMD) and cardiac arrhythmia that was only present in affected individuals. Compared to WT protein, POPDC1S191F exhibited recued cAMP affinity and impaired membrane trafficking, and overexpression of the mutant protein in murine cardiac cells altered action potential properties. Introduction of the homologous mutation into a zebrafish model produced both skeletal and cardiac muscle phenotypes that resembled those observed in patients. Together, these results reveal that a POPDC1 mutation is responsible for pathologies observed in a rare form of LGMD with cardiac arrhythmia. The accompanying image shows the tail musculature of popdc1S191F/S191F (top) and WT (bottom) zebrafish. Note the detachment and retraction of muscle fibers (actin, red) from the myotendinous junction (green, vinculin) in the mutant Popdc1-expressing animal.

Published December 7, 2015, by Corinne Williams

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POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking
Roland F.R. Schindler, … , Thomas Brand, Alessandra Ferlini
Roland F.R. Schindler, … , Thomas Brand, Alessandra Ferlini
Published January 4, 2016; First published December 7, 2015
Citation Information: J Clin Invest. 2016;126(1):239-253. https://doi.org/10.1172/JCI79562.
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Research Article Muscle biology

POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

Abstract

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 whole-exome 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.

Authors

Roland F.R. Schindler, Chiara Scotton, Jianguo Zhang, Chiara Passarelli, Beatriz Ortiz-Bonnin, Subreena Simrick, Thorsten Schwerte, Kar-Lai Poon, Mingyan Fang, Susanne Rinné, Alexander Froese, Viacheslav O. Nikolaev, Christiane Grunert, Thomas Müller, Giorgio Tasca, Padmini Sarathchandra, Fabrizio Drago, Bruno Dallapiccola, Claudio Rapezzi, Eloisa Arbustini, Francesca Romana Di Raimo, Marcella Neri, Rita Selvatici, Francesca Gualandi, Fabiana Fattori, Antonello Pietrangelo, Wenyan Li, Hui Jiang, Xun Xu, Enrico Bertini, Niels Decher, Jun Wang, Thomas Brand, Alessandra Ferlini

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