title: POPDC1(S201F) 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, 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.
authors.forename: Roland F R
authors.initials: RF
authors.lastname: Schindler
authors.forename: Chiara
authors.initials: C
authors.lastname: Scotton
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.forename: Chiara
authors.initials: C
authors.lastname: Passarelli
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ortiz-Bonnin
authors.forename: Subreena
authors.initials: S
authors.lastname: Simrick
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schwerte
authors.forename: Kar-Lai
authors.initials: KL
authors.lastname: Poon
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.forename: Susanne
authors.initials: S
authors.lastname: Rinné
authors.forename: Alexander
authors.initials: A
authors.lastname: Froese
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.forename: Christiane
authors.initials: C
authors.lastname: Grunert
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tasca
authors.forename: Padmini
authors.initials: P
authors.lastname: Sarathchandra
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Drago
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Claudio
authors.initials: C
authors.lastname: Rapezzi
authors.forename: Eloisa
authors.initials: E
authors.lastname: Arbustini
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Di Raimo
authors.forename: Marcella
authors.initials: M
authors.lastname: Neri
authors.forename: Rita
authors.initials: R
authors.lastname: Selvatici
authors.forename: Francesca
authors.initials: F
authors.lastname: Gualandi
authors.forename: Fabiana
authors.initials: F
authors.lastname: Fattori
authors.forename: Antonello
authors.initials: A
authors.lastname: Pietrangelo
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Brand
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D015815:Cell Adhesion Molecules; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D009124:Muscle Proteins; D049288:Muscular Dystrophies, Limb-Girdle / Q000209:etiology*; D009154:Mutation; D024683:Potassium Channels, Tandem Pore Domain / Q000032:analysis; D021381:Protein Transport; D015027:Zebrafish
chemical_list: D015815:Cell Adhesion Molecules; D000242:Cyclic AMP; D008565:Membrane Proteins; D009124:Muscle Proteins; D024683:Potassium Channels, Tandem Pore Domain; C530749:POPDC1 protein, human; C103742:potassium channel protein TREK-1