Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies

Abstract

Cardiomyopathy is an important cause of heart failure in Sub-Saharan Africa, accounting for up to 30% of adult heart failure hospitalisations. This high prevalence poses a challenge in societies without access to resources and interventions essential for disease management. Over 80 genes have been implicated as a cause of cardiomyopathy. Mutations in the phospholamban (PLN) gene are associated with dilated cardiomyopathy (DCM) and severe heart failure. In Africa, the prevalence of PLN mutations in cardiomyopathy patients is unknown. Our aim was to screen 315 patients with arrhythmogenic right ventricular cardiomyopathy (n = 111), DCM (n = 95), hypertrophic cardiomyopathy (n = 40) and peripartum cardiomyopathy (n = 69) for disease-causing PLN mutations by high resolution melt analysis and DNA sequencing. We detected the previously reported PLN c.25C > T (p.R9C) mutation in a South African family with severe autosomal dominant DCM. Haplotype analysis revealed that this mutation occurred against a different haplotype background to that of the original North American family and was therefore unlikely to have been inherited from a common ancestor. No other mutations in PLN were detected (mutation prevalence = 0.2%). We conclude that PLN is a rare cause of cardiomyopathy in African patients. The PLN p.R9C mutation is not well-tolerated, emphasising the importance of this gene in cardiac function.

Figure 1. Identification of the c.25C > T (p.R9C) PLN mutation.

(A) Electropherogram showing the c.25C > T sequence change. (B) Multiple species protein alignment of this sequence. (C) Pedigree of family DCM 320 showing variant c.25C > T and individuals with DCM. SB: Stillbirth; Gender (Square – Male; Circle – Female); Clinical Status (Black symbol – Affected; Clear symbol – Unaffected;? – Diagnosis uncertain); Mutation Status ( + – c.25C > T positive; – – c.25C > T negative).

Figure 2. Haplotype analysis.

(A) Pedigree of the DCM 320 family. (B) Pedigree of the MDO DCM family.