Mutations in the human phospholamban gene in patients with heart failure

Phospholamban (PLN) is a crucial Ca(2+) cycling protein and a primary mediator of the β-adrenergic effects resulting in enhanced cardiac output. Mutations in the gene encoding PLN have been associated with idiopathic dilated cardiomyopathy; however, no systematic search for PLN mutations in heart failure has been conducted.

We screened a cohort of 1,014 Brazilian patients with heart failure for mutations in the PLN gene. Molecular modeling studies of the mutations found were developed. Different disease etiologies were present in our sample: idiopathic, ischemic, Chagas, valvular, hypertensive, and others.

We identified 4 unrelated patients with PLN mutations (prevalence of 0.4%), 3 of them in the same amino acid residue (R9). Two patients presented a G-T missense mutation at the G26 nucleotide, which encodes an Arg-Leu substitution at codon 9 (R9L). One patient presented a G-A missense mutation at the same nucleotide, which encodes an Arg-His substitution at codon 9 (R9H). The fourth affected patient presented a T-G nonsense mutation at the nucleotide 116, substituting a termination codon for Leu-39 (L39stop). Molecular modeling studies suggested that R9L and R9H mutations might affect the region involved in protein kinase A docking and probably affect the mechanism modulating the release of phosphorylated PLN from the substrate binding site of protein kinase A.

Mutations in the PLN gene are a rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology. The Arg9 and Leu39 residues are the leading location of mutations described at this locus to date. Despite the few mutated residues described to date, the clinical spectrum of presentation appears to vary considerably.