== (AD) Confocal analysis of actin (phalloidin staining, red channel) and (AandC) DYS (green channel) or (BandD) vinculin (green channel) expression in trunk skeletal muscle of (AandB) WT (popdc1+/+) and (CandD) homozygous mutants (popdc1S191F/S191F). homologous mutation (popdc1S191F) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifiesPOPDC1as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic reasons for this heterogeneous group LY2119620 of inherited rare diseases. == Intro == The liaison between muscular dystrophy and heart dysfunction is well known in medical genetics. More than 90 muscular dystrophy phenotypes have been determined, of which most also display cardiac manifestations (13). Both dilated cardiomyopathies and cardiac arrhythmia phenotypes are often discovered as comorbidities and may even precede the onset of the muscle symptoms (46). The limb-girdle muscular dystrophies (LGMDs) are inherited diseases with onset after delivery and are characterized by progressive weakness and muscle atrophy predominantly affecting the hips, shoulders, and proximal extremity muscles (3). There are both autosomal dominant (LGMD1) and autosomal recessive (LGMD2) subtypes known. Today, a total of 31 different LGMD loci have been identified (7). A variety of mutations are known in the corresponding genes, which belong to several different cellular pathways, including sarcolemmal glycoproteins (dystroglycan and sarcoglycans), scaffolding proteins (caveolin-3 [CAV3]), and proteins involved in membrane repair and vesicle trafficking (dysferlin [DYSF] and anoctamin-5 [ANO5]) (7). POPDC1, which is also known asBVES, is a member of the Popeye domaincontaining (Popdc) gene LY2119620 family, encoding transmembrane proteins, which is highly expressed in cardiac and skeletal muscle in an overlapping manner (8, 9). POPDC proteins possess the evolutionarily conserved Popeye domain name, which functions as a high-affinity cAMP-binding site (8, 10). POPDC proteins are localized primarily at the plasma membrane and in t-tubules (10), although they have also been found at the nuclear envelope of striated muscle cells (11). An conversation of POPDC proteins with CAV3 and the 2-pore domain name potassium channel TREK-1 continues to be reported (10, 12). In the presence of POPDC proteins, TREK-1 currents are potentiated due to enhanced membrane trafficking (10). ThePopdc1null mutant in mice displays a retardation of muscle regeneration (13). Moreover, an impaired recovery from cardiac ischemia and an increase in infarct size have been described in thePopdc1null mutant (12). BothPopdc1andPopdc2null mutants display a stress-induced sinus node bradycardia, which develops in an age-dependent manner (10, 14). In zebrafish, popdc2morphants develop embryonic heart failure, atrioventricular (AV) prevent, and muscular dystrophy (15). Thus, both heart and skeletal muscle pathologies have been associated in model organisms with the lack of eitherPopdc1orPopdc2. However , so far, Popdcgenes have never been associated with human being hereditary diseases. We report here the identification of a homozygous recessive mutation inPOPDC1(c. 602C> To, p. S201F) by whole-exome sequencing (WES) in a family members with LGMD and AV block. We demonstrate that POPDC1S201Fhas strong pathogenic consequences, since it affects cAMP binding and LY2119620 subcellular localization from the mutant protein and its conversation partners. ThereforePOPDC1is a disease-causing gene associated with LGMD and cardiac arrhythmia. == Results == == POPDC1 is a disease-causing gene associated with cardiac disturbances and LGMD. == A family originating from a small Albanian enclave town of about three or more, 000 inhabitants located in Calabria (Italy) showed an interesting pseudodominant inheritance, compatible with consanguinity and geographic isolation (Figure 1A). The grandfather, 81 years old at the time of composing (PTI-1), started to complain of reduce limb-girdle weakness around the age of 40 and lost a chance to walk without aids around the age 60. At AGAP1 that time, blood creatine kinase (CK) was elevated (range, 7501300 IU/l). At the age of 60, a muscle biopsy was performed in his left deltoid muscle showing muscular dystrophy changes, with diameter variability, increased central nuclei, and the presence of a few.