TY - JOUR
T1 - POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking
AU - Schindler, Roland F R
AU - Scotton, Chiara
AU - Zhang, Jianguo
AU - Passarelli, Chiara
AU - Ortiz-Bonnin, Beatriz
AU - Simrick, Subreena
AU - Schwerte, Thorsten
AU - Poon, Kar Lai
AU - Fang, Mingyan
AU - Rinné, Susanne
AU - Froese, Alexander
AU - Nikolaev, Viacheslav O.
AU - Grunert, Christiane
AU - Müller, Thomas
AU - Tasca, Giorgio
AU - Sarathchandra, Padmini
AU - Drago, Fabrizio
AU - Dallapiccola, Bruno
AU - Rapezzi, Claudio
AU - Arbustini, Eloisa
AU - Romana Di Raimo, Francesca
AU - Neri, Marcella
AU - Selvatici, Rita
AU - Gualandi, Francesca
AU - Fattori, Fabiana
AU - Pietrangelo, Antonello
AU - Li, Wenyan
AU - Jiang, Hui
AU - Xu, Xun
AU - Bertini, Enrico Silvio
AU - Decher, Niels
AU - Wang, Jun
AU - Brand, Thomas
AU - Ferlini, Alessandra
PY - 2016/1/4
Y1 - 2016/1/4
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI79562
DO - 10.1172/JCI79562
M3 - Article
VL - 126
SP - 239
EP - 253
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 1
ER -