P.143 - POPDC1 gene mutation screening in patients with LGMD and heart disturbances: a mutation load effect?

Abstract

POPDC1 is the best-studied member of the Popeye domain-containing gene family. The members of this family encode transmembrane proteins, which are abundantly expressed in cardiac and skeletal muscle. The evolutionary conserved Popeye domain functions as a high-affinity 3'-5'-cyclic adenosine monophosphate (cAMP) binding domain. Recently, we identified recessive POPDC1 mutations in a family affected by Limb-girdle Muscular Dystrophy and atrioventricular (AV) block (OMIM LGMD2X). In order to evaluate if POPDC1 may contribute to phenotype variability in other LGMDs with or without cardiac involvement we screened by Sanger sequencing 166 patients with different phenotypes either orphan of gene mutations or with known gene mutations. We identified 8 different heterozygous POPDC1 mutations in 10 patients, 6 of them do also carry LMNA mutations, and 2 patients do carry Dysferlin mutations. Phenotypes vary from classical LGMD phenotype to pure cardiomyopathy with rhythm disturbances. It is emerging that the mutation load (occurrence of multiple mutations in different causative genes) plays a relevant role in phenotype modulation. We suggest that POPDC1 gene variations may contribute to the high clinical heterogeneity and intra- and interfamilial phenotypic variability of LMNA diseases. This hypothesis is supported by the known functional interaction between POPDC1 and LMNA.