OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency.
OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency.
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DOI：
10.1371/journal.pone.0138568
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Knöll R
中科院分区：
文献类型：
--
作者：
Marston S;Montgiraud C;Munster AB;Copeland O;Choi O;Dos Remedios C;Messer AE;Ehler E;Knöll R
对导致DCM突变的功能后果的研究仅限于少数已知突变的患者接受心脏移植的病例。为了增加用于直接研究的潜在组织样本的数量，我们对30例诊断为家族性扩张型心肌病的患者的心肌样本进行了全外显子测序，并筛选了58个HCM或DCM相关基因的潜在致病突变。我们在4个样本中鉴定了5个潜在致病的OBSCN突变;一个样本有两个OBSCN突变，一个突变被判断为与疾病无关。还鉴定了TTN中的6个截短突变，MYH 7中的3个突变，DSP中的2个突变，以及TNNC 1、TNNI 3、MYOM 1、VCL、GLA、PLB、TCAP、PKP 2和LAMA 4中各一个突变。与DCM样品相比，在健康供体样品中，obscurin mRNA的平均水平显著更高且更易变，但与OBSCN突变无关。在人心肌肌原纤维中观察到一条表观质量为960 ± 60 kDa的单一obscurin蛋白带。与没有OBSCN突变的DCM样品相比，具有OBSCN突变的三个样品具有显著更低水平的暗蛋白免疫反应性物质（对照水平的45±7、48±3和72±6%）dDCM对照、供体心脏和肌切除术样品中的暗蛋白水平是相同的。 OBSCN突变可通过单倍不足导致DCM表型的发展。暗蛋白基因的突变应被认为是DCM的重要致病因素，单独或与其他突变一起。
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. 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. 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.