Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension.
Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension.
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DOI：
10.1111/j.1399-0004.2009.01311.x
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发表时间：
2010-03
影响因子：
3.5
通讯作者：
Cogan JD
中科院分区：
文献类型：
--
作者：
Hamid R;Hedges LK;Austin E;Phillips JA 3rd;Loyd JE;Cogan JD
骨形态发生蛋白受体2型（BMPR2）基因突变是遗传性肺动脉高压（HPAH）的主要危险因素，HPAH是一种常染色体显性致命疾病。我们之前已经证明，含有过早终止密码子（PTC）突变的BMPR2转录本通过无义介导的衰变（NMD）迅速且几乎完全降解。在这里，我们报告了一个独特的PTC突变（W13X），它没有以预测的方式表现。我们发现患者来源的培养淋巴细胞（CLs）含有易检测水平的ptc -含转录物。进一步分析表明，该转录物通过下游Kozak序列的翻译再起始逃脱了NMD，导致173个氨基酸缺失。用氨基糖苷处理含有PTC的CLs降低了截断的蛋白水平，全长BMPR2蛋白和重要的BMPR-II信号的相互增加。这是氨基糖苷介导的BMPR2突变在患者源性细胞蛋白水平上的“修复”的首次证明，对于没有疾病特异性治疗方案的HPAH治疗具有明显的意义。我们的数据还表明，在仅仅根据测序数据将突变标记为单倍体不足或显性阴性之前，需要对突变进行更彻底的表征。
Bone morphogenetic protein receptor type 2 (BMPR2 ) gene mutations are a major risk factor for heritable pulmonary arterial hypertension (HPAH), an autosomal dominant fatal disease. We have previously shown that BMPR2 transcripts that contain premature termination codon (PTC) mutations are rapidly and nearly completely degraded through nonsense mediated decay (NMD). Here we report a unique PTC mutation (W13X) that did not behave in the predicted manner. We found that patient-derived cultured lymphocytes (CLs) contained readily detectable levels of the PTC-containing transcript. Further analysis suggested that this transcript escaped NMD by translational re-initiation at a downstream Kozak sequence, resulting in the omission of 173 amino acids. Treatment of CLs containing the PTC with an aminoglycoside decreased the truncated protein levels, with a reciprocal increase in full-length BMPR2 protein and, importantly, BMPR-II signaling. This is the first demonstration of aminoglycoside-mediated ‘repair’ of a BMPR2 mutation at the protein level in patient-derived cells and has obvious implications for treatment of HPAH where no disease-specific treatment options are available. Our data also suggest the need for a more thorough characterization of mutations prior to labeling them as haploinsufficient or dominant negative based simply on sequencing data.
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