TY  - JOUR
CY  - London
TI  - EIF2AK4 mutation as ?second hit? in hereditary pulmonary arterial hypertension
PB  - BioMed Central
SN  - 1465-993X
ID  - heidok22094
VL  - 17
IS  - 141
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/22094/
N2  - Background: Mutations in the eukaryotic translation initiation factor 2? 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.   Methods: 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.   Results: 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.   Conclusions: 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.
SP  - 1
Y1  - 2016///
AV  - public
EP  - 8
JF  - Respiratory Research
A1  - Eichstaedt, Christina A.
A1  - Song, Jie
A1  - Benjamin, Nicola
A1  - Harutyunova, Satenik
A1  - Fischer, Christine
A1  - Grünig, Ekkehard
A1  - Hinderhofer, Katrin
ER  -