EIF2AK4 Mutations in Pulmonary Capillary Hemangiomatosis
EIF2AK4 Mutations in Pulmonary Capillary Hemangiomatosis
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DOI：
10.1378/chest.13-2366
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发表时间：
2014-02-01
期刊：
影响因子：
9.6
通讯作者：
Elliott, C. Gregory
中科院分区：
文献类型：
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作者：
Best, D. Hunter;Sumner, Kelli L.;Elliott, C. Gregory
背景：肺毛细血管瘤病（PCH）是一种罕见的原因不明的毛细血管增生疾病，死亡率高。有多名PCH患者的家庭提示有遗传原因，尽管遗传病因尚不清楚。方法：我们使用外显子组测序在一个有两个患病兄弟的家庭中鉴定PCH的候选基因。然后，我们筛选了11名家族性（n = 1）或散发性（n = 10） PCH患者进行突变。结果：通过外显子组测序，我们在两个患病兄弟中鉴定了真核翻译起始因子2 a激酶4 (EIF2AK4)（以前称为GCN2）的复合突变。父母和一个未受影响的妹妹都是杂合携带者。此外，我们在10名无亲缘关系的散发性PCH患者中分别鉴定出2个EIF2AK4突变。EIF2AK4属于一个激酶家族，在细胞应激反应中调节血管生成。结论：EIF2AK4基因突变可能在家族性和部分非家族性病例中引起常染色体隐性PCH。
Background: Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown. Methods: We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations.Results: Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 a kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress.Conclusions: Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.