COL4A2 Mutations Impair COL4A1 and COL4A2 Secretion and Cause Hemorrhagic Stroke
COL4A2 Mutations Impair COL4A1 and COL4A2 Secretion and Cause Hemorrhagic Stroke
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DOI：
10.1016/j.ajhg.2011.11.022
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发表时间：
2012-01-13
影响因子：
9.8
通讯作者：
Gould, Douglas B.
中科院分区：
文献类型：
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作者：
Jeanne, Marion;Labelle-Dumais, Cassandre;Gould, Douglas B.
胶原，IV型，α 1 （COL4A1）和α 2 （COL4A2）形成异源三聚体，是基底膜，包括脑血管膜的丰富成分。COL4A1突变越来越被认为是多系统疾病的原因，包括高渗透性脑血管疾病和脑出血（ICH）。由于COL4A1和COL4A2在结构和功能上是相关的，我们假设COL4A2的变异也会导致脑出血。我们对96名脑出血患者的COL4A2进行测序，并在4名患者中发现了3种罕见的非同义编码变体，这些变体在144名无脑出血患者中不存在。这三种变体都改变了进化上保守的氨基酸。通过细胞分析，我们发现这些假定的突变导致COL4A1和COL4A2在细胞内积聚，以牺牲它们的分泌为代价，这支持了它们的致病性。此外，我们发现Col4a2突变小鼠也具有完全渗透的ICH，并且小鼠和人类的突变导致COL4A1和Col4a2在内质网（ER）内保留。重要的是，在患者身上发现的三个假定突变中的两个触发内质网应激并激活未折叠蛋白反应。鉴定可能导致人类患者脑出血的推定COL4A2突变提供了对这种疾病的致病机制的深入了解。我们的数据表明，COL4A2突变损害COL4A1和COL4A2的分泌，也可能导致细胞毒性。最后，我们的研究结果表明，COL4A1和COL4A2的突变共同导致了散发的脑出血病例。
Collagen, type IV, alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers and are abundant components of basement membranes, including those of the cerebral vasculature. COL4A1 mutations are an increasingly recognized cause of multisystem disorders, including highly penetrant cerebrovascular disease and intracerebral hemorrhage (ICH). Because COL4A1 and COL4A2 are structurally and functionally associated, we hypothesized that variants in COL4A2 would also cause ICH. We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals. All three variants change evolutionarily conserved amino acids. Using a cellular assay, we show that these putative mutations cause intracellular accumulation of COL4A1 and COL4A2 at the expense of their secretion, which supports their pathogenecity. Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH and that mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER). Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response. The identification of putative COL4A2 mutations that might contribute to ICH in human patients provides insight into the pathogenic mechanisms of this disease. Our data suggest that COL4A2 mutations impair COL4A1 and COL4A2 secretion and can also result in cytotoxicity. Finally, our findings suggest that, collectively, mutations in COL4A1 and COL4A2 contribute to sporadic cases of ICH.