1. POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking
- Author
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Hui Jiang, Francesca Romana Di Raimo, Subreena Simrick, Giorgio Tasca, Jianguo Zhang, Fabiana Fattori, C. Scotton, Claudio Rapezzi, Thomas Brand, Bruno Dallapiccola, Rita Selvatici, Niels Decher, Alexander Froese, Viacheslav O. Nikolaev, Antonello Pietrangelo, Roland F.R. Schindler, Jun Wang, Fabrizio Drago, Enrico Bertini, Susanne Rinné, Marcella Neri, Alessandra Ferlini, Thorsten Schwerte, Kar Lai Poon, Thomas Müller, Christiane Grunert, Wenyan Li, Eloisa Arbustini, Mingyan Fang, Xun Xu, Chiara Passarelli, Beatriz Ortiz-Bonnin, Padmini Sarathchandra, Francesca Gualandi, Schindler, Roland F. R., Scotton, Chiara, Zhang, Jianguo, Passarelli, Chiara, Ortiz-Bonnin, Beatriz, Simrick, Subreena, Schwerte, Thorsten, Poon, Kar-Lai, Fang, Mingyan, Rinné, Susanne, Froese, Alexander, Nikolaev, Viacheslav O., Grunert, Christiane, Müller, Thoma, Tasca, Giorgio, Sarathchandra, Padmini, Drago, Fabrizio, Dallapiccola, Bruno, Rapezzi, Claudio, Arbustini, Eloisa, Romana Di Raimo, Francesca, Neri, Marcella, Selvatici, Rita, Gualandi, Francesca, Fattori, Fabiana, Pietrangelo, Antonello, Li, Wenyan, Jiang, Hui, Xu, Xun, Bertini, Enrico, Decher, Niel, Wang, Jun, Brand, Thoma, Ferlini, Alessandra, Medical Research Council (MRC), British Heart Foundation, and The Magdi Yacoub Institute
- Subjects
0301 basic medicine ,Male ,Pathology ,Muscle Proteins ,Research & Experimental Medicine ,DOMAIN-CONTAINING PROTEINS ,domain containing proteins ,Membrane Potentials ,Cyclic AMP ,Missense mutation ,Muscular dystrophy ,Child ,Zebrafish ,Membrane Protein ,Cardiac muscle cell ,Aged, 80 and over ,biology ,Medicine (all) ,Aged ,Animals ,Arrhythmias, Cardiac ,Humans ,Membrane Proteins ,Middle Aged ,Muscular Dystrophies, Limb-Girdle ,Mutation ,Potassium Channels, Tandem Pore Domain ,Protein Transport ,STRESS-MEDIATED MODULATION ,General Medicine ,11 Medical And Health Sciences ,medicine.anatomical_structure ,Medicine, Research & Experimental ,SKELETAL-MUSCLE ,HEART ,POTASSIUM CHANNEL ,muscular dystrophy ,arrhythmia ,ITGA7 ,Life Sciences & Biomedicine ,Human ,Research Article ,medicine.medical_specialty ,HL-1 CELLS ,Immunology ,cardiac pacemakin ,Membrane Potential ,NO ,HL1 cell ,03 medical and health sciences ,Internal medicine ,medicine ,KINASE ,Allele ,skeletal muscle ,Science & Technology ,COMPLEX ,Animal ,Cardiac arrhythmia ,Skeletal muscle ,stress mediated modulation, domain containing proteins, skeletal muscle, cardiac pacemakin, potassium channel, HL1 cell, zebrafish, heart, kinase ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Endocrinology ,stress mediated modulation ,CARDIAC PACEMAKING ,Cell Adhesion Molecules - 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, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1(S201F) 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 (popdc1(S191F)) 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. peerReviewed
- Published
- 2014