EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension
EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension
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DOI：
10.1038/ng.2844
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发表时间：
2014-01-01
期刊：
影响因子：
30.8
通讯作者：
Soubrier, Florent
中科院分区：
文献类型：
--
作者：
Eyries, Melanie;Montani, David;Soubrier, Florent
肺静脉闭塞性疾病（PVOD）是肺动脉高压的一种罕见和破坏性原因，其组织学特征为间隔静脉和间隔前小静脉的广泛纤维内膜增生，通常与肺毛细血管扩张和增殖相关（1，2）。在目前的肺动脉高压分类中，PVOD被归类为单独的肺动脉高压相关组（3）。PVOD呈偶发性或家族性病例，似乎是隐性传播方式（4）。使用全外显子组测序，我们检测到EIF2AK4（也称为GCN 2）的隐性突变，在所有13个研究的家庭中与PVOD共分离。我们还发现在20例组织学证实的散发性PVOD病例中有5例存在EIF2AK4双等位基因突变。所有突变，无论是纯合还是复合杂合状态，都破坏了基因的功能。这些发现指出EIF2AK4是与PVOD发展相关的主要基因，有助于理解肺动脉高压的复杂遗传结构。
Pulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension that is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules and is frequently associated with pulmonary capillary dilatation and proliferation(1,2). PVOD is categorized into a separate pulmonary arterial hypertension-related group in the current classification of pulmonary hypertension(3). PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission(4). Using whole-exome sequencing, we detected recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied. We also found biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD. All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene. These findings point to EIF2AK4 as the major gene that is linked to PVOD development and contribute toward an understanding of the complex genetic architecture of pulmonary hypertension.