POPDC3 gene variants associate with a new form of limb girdle muscular dystrophy

OBJECTIVE: The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cAMP signaling. Besides gastric cancer, no disease association has been described. We here describe a new muscular dystrophy associated with this gene. METHODS: 1,500 patients with unclassified limb girdle weakness or hyperCKemia were screened for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle MRI, muscle biopsy and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK-1 current. RESULTS: We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe and p.Arg261Gln) in five patients from three ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy-terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands' muscle biopsies were dystrophic and serum creatine kinase levels were 1,050-9,200 U/L. Muscle weakness was proximal with adulthood onset in most patients, affecting lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles, while cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using two different splice-site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All three mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1. INTERPRETATION: Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy.