Abstract for presentation at 11th International Congress of Human Genetics

Leu39Ter mutation identified in the phospholamban gene in a patient with hypertrophic cardiomyopathy

  • Ms Christine Chiu, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Australia
  • Joanne Lind, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Australia
  • Ms Jodie Ingles, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Australia
  • Dr Jonathan Arthur, Central Clinical School, Faculty of Medicine, University of Sydney & Sydney Uni Biological Informatics and Technology Centre, Australia
  • A/Prof Christopher Semsarian, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute & Department of Cardiology, Royal Prince Alfred Hospital, NSW, Australia

    • Purpose: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder. Genetic screening of the 8 most common sarcomeric genes known to cause HCM, results in no mutation being identified in up to 60% of cases, indicating other genes account for the remainder of cases. Given the role of calcium homeostasis in the pathogenesis of HCM, this study screened the phospholamban (PLB) gene, a regulator of calcium entry into the sarcoplasmic reticulum, for causative mutations in a large HCM cohort.
    Methods: Patients referred to the HCM Clinic at RPAH, Sydney were included in this study. Genomic DNA was extracted and the coding exon of the PLB gene was amplified by PCR and products were screened for sequence variants using high-performance liquid chromatography, followed by direct DNA sequencing and/or restriction enzyme digestion in selected cases.
    Results: From 308 HCM probands studied, one sequence variant was identified in a 65y.o. female patient with mild clinical disease. The variant changed a conserved amino acid at codon 39 from a leucine to a termination codon (Leu39Stop), resulting in a truncated protein. The patient was heterozygous for the PLB mutation. This variant was not identified in over 100 healthy controls. No other variants were identified in the PLB gene in the remaining probands.
    Conclusion: The heterozygous Leu39Stop mutation in the PLB gene is a rare mutation that leads to the development of HCM. Previous studies have shown individuals homozygous for this mutation develop dilated cardiomyopathy. These findings strongly suggest PLB function and regulation of calcium homeostasis are important in the pathogenesis of cardiomyopathies. PLB should therefore be considered as a candidate gene when screening HCM cohorts.

    Conference Organiser - ICMS Pty Ltd