POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking
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
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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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 2

Membrane trafficking of POPDC1 is affected in muscle biopsies.

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Membrane trafficking of POPDC1 is affected in muscle biopsies. Skeletal ...
Skeletal muscle biopsies of PTI-1 and PTIII-1 and 2 controls were immunostained for (A–D) POPDC1 (green signal) and SCGA (red signal). (E) The immunofluorescence signals were quantified in 10 muscle fibers of 3 sections per biopsy. The signals of POPDC1 and SGCA and the ratio of both were plotted relative to the means of both controls, which were set at 1. (F–Q) Subcellular localization of POPDC1 in (F–H) CT1, (I–K) CT2, (L–N) PTI-1, and (O–Q) PTIII-2. Perinuclear localization of POPDC1 is only weakly present in control samples, whereas in patients’ muscle biopsies, a significant perinuclear accumulation of the mutant protein was seen. Scale bars: 10 μm (A–D, G, H, J, K, M, N, P, and Q); 20 μm (F, I, L, and O). (R and S) Western blot analysis of (R) POPDC1 expression in skeletal muscle biopsies and of (S) POPDC1 and POPDC2 in dermal fibroblasts of 2 controls (CT1 and CT2) and PTI-1 and PTIII-2. The main POPDC1 isoform in R is labeled by POPDC1. Additional isoforms are indicated by arrows, while bands, which are considered to be unspecific and remain present after peptide competition (Supplemental Figure 4, A and B), are indicated by an asterisk. Results are representative of 3 independent experiments.