Pneumologie 2018; 72(S 01): S114
DOI: 10.1055/s-0037-1619430
Sektion 14 – Zellbiologie
Posterbegehung – Titel: Posterbegehung der Sektion Zellbiologie
Georg Thieme Verlag KG Stuttgart · New York

BMPR2 gene promoter variants analysis in pulmonary arterial hypertension

J Song
1   Centre for Pulmonary Hypertension at the Thoraxclinic Heidelberg, University Hospital Heidelberg, Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL); Institute of Human Genetics, Heidelberg University
,
C Eichstaedt
1   Centre for Pulmonary Hypertension at the Thoraxclinic Heidelberg, University Hospital Heidelberg, Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL); Institute of Human Genetics, Heidelberg University
,
R Rodríguez Viales
2   European Molecular Biology Laboratory Heidelberg
,
Z Pan
3   Centre for Pulmonary Hypertension at the Thoraxclinic Heidelberg, University Hospital Heidelberg
,
C Fischer
4   Institut für Humangenetik, Universität Heidelberg
,
K Hinderhofer
4   Institut für Humangenetik, Universität Heidelberg
,
E Grünig
3   Centre for Pulmonary Hypertension at the Thoraxclinic Heidelberg, University Hospital Heidelberg
› Author Affiliations
Further Information

Publication History

Publication Date:
21 February 2018 (online)

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    Background:

    Mutations have been identified in the bone morphogenetic protein type II (BMPR2) gene as a predominant PAH causing gene in about 85% heritable PAH (HPAH) and 25% of idiopathic PAH (IPAH) cases. However, the penetrance of BMPR2 is only about 27% indicating that other modifiers such as promoter variants may contribute to disease manifestation. Variants of the BMPR2 promoter have been identified previously as a second hit in a family with autosomal dominantly inherited PAH.

    Objectives:

    The aim of this study was to identify BMPR2 promoter variants in HPAH and sporadic patients and to analyse their transcriptional effect on the BMPR2 gene expression in human pulmonary artery smooth muscle cells (HPASMCs).

    Methods:

    BMPR2 promoter variants have been screened by direct Sanger sequencing in IPAH/HPAH patients and their effect investigated on BMPR2 expression. The BMPR2 promoter regions containing identified variants were amplified together with the wild-type promoter and cloned into the pGL4.10 vector fused with a luciferase reporter gene. Recombinant plasmids were transfected into HPASMCs and transcriptional activity was assessed.

    Results:

    Nine different BMPR2 promoter variants were identified in PAH families and IPAH patients by Sanger sequencing. In the functional analysis, seven of the nine variants (c.-575A>T, c.-586dupT, c.-910C>T, c.-1141C>T, c.-930_-928dupGGC, c.-933_-928dupGGCGGC and c.-930_-928delGGC) led to a significantly decreased transcriptional activity in comparison to the wild-type. In addition, in silico analyses revealed that these seven variants may have an impact on BMPR2 function in patients.

    Conclusions:

    This study showed new variants in the BMPR2 promoter region which might functionally affect the BMPR2 gene expression. Further studies are needed to investigate frequencies of BMPR2 promoter variants and their impact on penetrance/disease manifestation.


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