<i>OBSCN</i> Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency

<div><p>Background</p><p>Studies of the functional consequences of DCM-causing mutations have been limited to a few cases where patients with known mutations had heart transplants. To increase the number of potential tissue samples for direct investigation we performed whole exon sequencing of explanted heart muscle samples from 30 patients that had a diagnosis of familial dilated cardiomyopathy and screened for potentially disease-causing mutations in 58 HCM or DCM-related genes.</p><p>Results</p><p>We identified 5 potentially disease-causing <i>OBSCN</i> mutations in 4 samples; one sample had two <i>OBSCN</i> mutations and one mutation was judged to be not disease-related. Also identified were 6 truncating mutations in <i>TTN</i>, 3 mutations in <i>MYH7</i>, 2 in <i>DSP</i> and one each in <i>TNNC1</i>, <i>TNNI3</i>, <i>MYOM1</i>, <i>VCL</i>, <i>GLA</i>, <i>PLB</i>, <i>TCAP</i>, <i>PKP2</i> and <i>LAMA4</i>. The mean level of obscurin mRNA was significantly greater and more variable in healthy donor samples than the DCM samples but did not correlate with <i>OBSCN</i> mutations. A single obscurin protein band was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The three samples with <i>OBSCN</i> mutations had significantly lower levels of obscurin immunoreactive material than DCM samples without <i>OBSCN</i> mutations (45±7, 48±3, and 72±6% of control level).Obscurin levels in DCM controls, donor heart and myectomy samples were the same.</p><p>Conclusions</p><p><i>OBSCN</i> mutations may result in the development of a DCM phenotype via haploinsufficiency. Mutations in the obscurin gene should be considered as a significant causal factor of DCM, alone or in concert with other mutations.</p>