Background
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.
Results
We identified 5 potentially disease-causing OBSCN mutations in 4 samples; one sample
had two OBSCN mutations and one mutation was judged to be not disease-related. Also
identified were 6 truncating mutations in TTN, 3 mutations in MYH7, 2 in DSP and one each
in TNNC1, TNNI3, MYOM1, VCL, GLA, PLB, TCAP, PKP2 and LAMA4. 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 OBSCN mutations. A single obscurin protein
band was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The three
samples with OBSCN mutations had significantly lower levels of obscurin immunoreactive
material than DCM samples without OBSCN mutations (45±7, 48±3, and 72±6% of control
level).Obscurin levels in DCM controls, donor heart and myectomy samples were the same.
Conclusions
OBSCN 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.