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 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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Figure 5

POPDC1S201F hyperpolarizes the membrane potential of spontaneously beating HL-1 cells.

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POPDC1S201F hyperpolarizes the membrane potential of spontaneously beati...
(A) Representative action potentials recorded for HL-1 cells or HL-1 cells transfected with POPDC1 or POPDC1S201F. The boxes at the bottom represent an enlarged view to show the effects on maximal hyperpolarization and afterhyperpolarization. (B) Analyses of the action potential duration, analyzed at 50 % of repolarization (APD50). (C) Analyses of maximal hyperpolarization (Max. HP), (D) afterhyperpolarization (AHP), and (E) activation threshold for HL-1 cells or HL-1 cells transfected with POPDC1 or POPDC1S201F. (F) Enlarged view showing the upstroke phase of an action potential of HL-1 cells or HL-1 cells transfected with POPDC1 or POPDC1S201F. Traces were aligned to the activation threshold. (G) Analyses of the upstroke velocity (Up. vel.). Results are presented as mean ± SEM. One-way ANOVA was used to compare multiple variables presented in B–E and G. **P < 0.01; ***P < 0.001.