EXCLUSION OF DYSTROPHIN AS A CANDIDATE GENE IN A FAMILY WITH X-LINKED DILATED CARDIOMYOPATHY
J.K. French*, D. Wilson, D.R. Love.
Department of Cardiology, Green Lane Hospital, and University of Auckland, Auckland, New Zealand.
Dilated cardiomyopathy (DCM) is familial in approximately 20-30% of cases. Of the inherited forms, X-linked DCM affects males in their teens or early twenties due to severe and rapidly progressive myocardial dysfunction; serum creatine kinase levels are variably elevated. In X-linked DCM three mutation events have been reported (promoter, splice-site and missense) in the dystrophin gene.
We studied a family with apparent X-linked DCM. Both brothers presented with heart failure aged 16 years. The probands' sister, mother, father and maternal aunts were clinically, electrocardiographically, and echocardiographically normal. Linkage analysis did not exclude dystrophin as a candidate gene so we devised the following sequencing strategy: isolation of total RNA from the probands lymphoblasts, nested RT-PCR amplification of overlapping 1kb fragments encompassing the entire 11kb of coding sequence; and complete double-stranded sequencing of the gel-purified amplification products using further nested primers. Assembly of the ten overlapping contiguous PCR product sequences revealed a range of amino acid variants including a novel polymorphism. However, none of these variants in the dystrophin gene can account for the DCM phenotype.
Conclusion: Dystrophin has been excluded as a candidate gene in this family, suggesting X-linking DCM is genotypically heterogeneous. We are investigating sarcoglycans (dystrophin-associated proteins) as possible candidate gene loci.
