LGMD AUTOSOMAL RESSESSIVE AND DOMINANT: P.100BVES loss-of-function mutations in limb-girdle muscular dystrophy 2X with cardiac conduction disorders

Abstract

BVES encodes for a 360 amino acid protein also known as POPDC1, which is part of the Popeye domain containing (POPDC) family of proteins. POPDC1, POPDC2 and POPDC3 are cAMP-binding transmembrane proteins that are abundantly expressed in striated muscle. A homozygous missense mutation (p.Ser201Phe) in BVES has been identified in three individuals from one single family, the eldest presenting with an overt limb-girdle muscular dystrophy phenotype and all three of them showing an elevated creatine kinase (CK) level and a second-degree atrioventricular (AV) block. The disease was classified as LGMD2X. We performed whole exome sequencing (WES) in a large cohort of patients with unexplained limb-girdle muscular weakness (LGMW) and/or an elevated CK level. Immunohistochemical, Western blotting and mRNA experiments of patients' skeletal muscle tissue were performed to study the pathogenicity of identified loss-of-function (LOF) variants in BVES. We identified 4 individuals from 3 families harboring homozygous LOF variants in BVES. Patients showed skeletal muscle and cardiac conduction abnormalities of varying nature and severity, but exhibited at least subclinical signs of both skeletal muscle and cardiac involvement. Identification of LOF mutations in BVES, causing an adult-onset skeletal muscle disorder with concomitant cardiac conduction disorders, underlines the role of POPDC family, and POPDC1 in particular, in striated muscle disease. This recessive disorder linked to mutations in BVES appears of low prevalence, but is probably underdiagnosed due to its striking phenotypic variability and often subtle yet clinically relevant manifestations, particularly concerning the cardiac involvement.