EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension.
EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension.
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DOI：
10.1186/s12931-016-0457-x
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发表时间：
2016-11-04
影响因子：
5.8
通讯作者：
Hinderhofer K
中科院分区：
文献类型：
--
作者：
Eichstaedt CA;Song J;Benjamin N;Harutyunova S;Fischer C;Grünig E;Hinderhofer K
真核翻译起始因子2α激酶4 （EIF2AK4）基因突变最近在隐性遗传的静脉闭塞性疾病中被发现。在这项研究中，我们评估了EIF2AK4突变是否也发生在常染色体显性遗传性肺动脉高压（HPAH）和骨形态发生蛋白受体2 （BMPR2）突变不完全外显的家庭中。临床检查包括体格检查、心电图、（应激）超声心动图和肺功能。3例患者经右心导管确认明显多环芳烃。遗传分析采用新的多环芳烃特异性基因面板分析，对所有已知多环芳烃和进一步的候选基因进行下一代测序。通过Sanger测序确认鉴定的变异。所有患有明显HPAH的在世家族成员都携带两种致病性杂合突变：BMPR2基因的框架移位突变和EIF2AK4基因的新型剪接位点突变。仅携带BMPR2突变的两名家庭成员未发生明显的HPAH。这是首次有研究表明EIF2AK4也可能导致常染色体显性遗传的HPAH。到目前为止，它只被确定为隐性形式的HPAH。只有同时出现两种突变的家庭成员才会出现明显的HPAH。因此，EIF2AK4和BMRPR2突变支持“二次命中”假说，解释了该家族中HPAH的不同外显率。因此，评估已知突变家族中所有已知的多环芳烃基因可能有助于预测迄今为止未受影响的突变携带者的临床表现。
Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have recently been identified in recessively inherited veno-occlusive disease. In this study we assessed if EIF2AK4 mutations occur also in a family with autosomal dominantly inherited pulmonary arterial hypertension (HPAH) and incomplete penetrance of bone morphogenic protein receptor 2 (BMPR2) mutations. Clinical examinations in a family with 10 members included physical examination, electrocardiogram, (stress)-echocardiography and lung function. Manifest PAH was confirmed by right heart catheterisation in three affected subjects. Genetic analysis was performed using a new PAH-specific gene panel analysis with next generation sequencing of all known PAH and further candidate genes. Identified variants were confirmed by Sanger sequencing. All living family members with manifest HPAH carried two pathogenic heterozygous mutations: a frame shift mutation in the BMPR2 gene and a novel splice site mutation in the EIF2AK4 gene. Two family members who carried the BMPR2 mutation only did not develop manifest HPAH. This is the first study suggesting that EIF2AK4 can also contribute to autosomal dominantly inherited HPAH. Up to now it has only been identified in a recessive form of HPAH. Only those family members with a co-occurrence of two mutations developed manifest HPAH. Thus, the EIF2AK4 and BMRPR2 mutations support the “second hit” hypothesis explaining the variable penetrance of HPAH in this family. Hence, the assessment of all known PAH genes in families with a known mutation might assist in predictions about the clinical manifestation in so far non-affected mutation carriers.
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影响因子：
30.8
作者：
Eyries, Melanie;Montani, David;Soubrier, Florent
通讯作者：
Soubrier, Florent
DOI：
10.1056/nejmra0809889
发表时间：
2010-05-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
5
作者：
Gomez, Juan;Reguero, Julian R.;Coto, Eliecer
通讯作者：
Coto, Eliecer
影响因子：
9.6
作者：
Best, D. Hunter;Sumner, Kelli L.;Elliott, C. Gregory
通讯作者：
Elliott, C. Gregory
影响因子：
24.3
作者：
Montani, David;Lau, Edmund M.;Humbert, Marc
通讯作者：
Humbert, Marc