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@article{Schindler:2016:10.1172/JCI79562,
author = {Schindler, RF and Scotton, C and Zhang, J and Passarekki, C and Ortiz-Bonnin, B and Simrick, S and Schwerte, T and Poon, KL and Fang, M and Rinne, S and Froese, A and Nikolaev, VO and Grunert, C and Müller, T and Tasca, G and Sarathchandra, P and Drago, F and Dallapiccola, B and Rapezzi, C and Arbustini, E and Romana, di Raimo F and Neri, M and Selvatici, R and Gualandi, F and Fattori, F and Pietrangolo, A and Li, W and Jiang, H and Xu, X and Bertini, E and Decher, N and Wang, J and Brand, T and Ferlini, A},
doi = {10.1172/JCI79562},
journal = {Journal of Clinical Investigation},
pages = {239--253},
title = {POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking},
url = {http://dx.doi.org/10.1172/JCI79562},
volume = {126},
year = {2016}
}

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TY  - JOUR
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 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.
AU  - Schindler,RF
AU  - Scotton,C
AU  - Zhang,J
AU  - Passarekki,C
AU  - Ortiz-Bonnin,B
AU  - Simrick,S
AU  - Schwerte,T
AU  - Poon,KL
AU  - Fang,M
AU  - Rinne,S
AU  - Froese,A
AU  - Nikolaev,VO
AU  - Grunert,C
AU  - Müller,T
AU  - Tasca,G
AU  - Sarathchandra,P
AU  - Drago,F
AU  - Dallapiccola,B
AU  - Rapezzi,C
AU  - Arbustini,E
AU  - Romana,di Raimo F
AU  - Neri,M
AU  - Selvatici,R
AU  - Gualandi,F
AU  - Fattori,F
AU  - Pietrangolo,A
AU  - Li,W
AU  - Jiang,H
AU  - Xu,X
AU  - Bertini,E
AU  - Decher,N
AU  - Wang,J
AU  - Brand,T
AU  - Ferlini,A
DO  - 10.1172/JCI79562
EP  - 253
PY  - 2016///
SN  - 1558-8238
SP  - 239
TI  - POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking
T2  - Journal of Clinical Investigation
UR  - http://dx.doi.org/10.1172/JCI79562
UR  - https://www.jci.org/articles/view/79562
UR  - http://hdl.handle.net/10044/1/27455
VL  - 126
ER  -

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