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

Untangling the complexity of limb‐girdle muscular dystrophies

“…An LGMD phenotype can also be caused by mutations in nuclear envelope proteins, which include lamin A/C ( LMNA , LGMD1B), transportin 3 ( TNPO3 , LGMD1F), Popeye domain–containing protein 1 ( POPDC1 , LGMD2X), and lamina‐associated polypeptide 1B ( LAP1B , LGMD2Y) . POPDC1 is present not only in the nuclear envelope but also in the sarcolemma and t‐tubules . All nuclear envelopathy LGMD variants, except transportinopathy‐3, affect the heart.…”

“…All nuclear envelopathy LGMD variants, except transportinopathy‐3, affect the heart. Early contractures have been reported in all nuclear envelopathy LGMD variants, except POPDC1‐opathy, but only a single family with this latter muscular dystrophy has been reported . Mutations in LMNA cause not only muscular dystrophies (congenital muscular dystrophy, EDMD, and LGMD1B), but also other disorders affecting nonmuscle tissues (adipose tissue, bone, skin, and peripheral nerve), collectively called laminopathy .…”

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

“…Genes involved in currently recognized types of LGMD often affect sarcolemmal glycoproteins, proteins that glycosylate sarcolemmal and scaffolding proteins, and proteins involved in membrane repair and vesicle trafficking in muscle . In 2016, pathogenic variants in POPDC1 , a member of the new family of proteins encoded by the Popeye domain containing (POPDC) genes, were identified in a family with primary symptoms of cardiac arrhythmia and only mild or no muscle affection (OMIM #616812, LGMDR25, previously classified as LGMD2X) . These findings have recently been corroborated in 4 other individuals from 3 families .…”

Popdc1/Bves Functions in the Preservation of Cardiomyocyte Viability While Affecting Rac1 Activity and Bnip3 Expression

“…In skeletal muscle, Popdc1/Bves plays a role in tissue regeneration and myoblast fusion while in the heart, Popdc1/Bves has been found to be important for the control of heart rate under stress, the recovery from ischemia/reperfusion injury and the development of ischemic and pharmacologic preconditioning [Andree et al, ; Froese et al, ; Alcalay et al, ]. In the human heart, Popdc1/Bves is markedly reduced during end stage heart failure and mutated Popdc1/Bves has been identified in patients born with Fallot's tetralogy and with muscular dystrophy [Gingold‐Belfer et al, ; Wu et al, ; Schindler et al, ], suggesting its involvement in heart pathology and morphogenesis. The ability of Popdc1/Bves to interact with ion channels and bind cAMP [Froese et al, ], as well as the presence of Popdc1/Bves in the caveolae and its interaction with caveolin3 [Alcalay et al, ], provide a partial description of mechanisms underlying the functional deficits reported in hearts lacking Popdc1/Bves.…”