Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14.

Tom G W Letteboer,Cornelius J J Westermann,Kechen Zhau,Johannes K P Van Amstel,Sophie Dupuis-Girod,David M Jablons,Christopher B Merrick,Michael Benzinou,Jonathan H Berg,Rosemary J Akhurst,Minh D To,David A Quigley,Allan Balmain,Il-Jin Kim,Gaetan Lesca,Sophie Giraud

doi:10.3389/fgene.2015.00067

Abstract

HHT shows clinical variability within and between families. Organ site and prevalence of arteriovenous malformations (AVMs) depend on the HHT causative gene and on environmental and genetic modifiers. We tested whether variation in the functional ENG allele, inherited from the unaffected parent, alters risk for pulmonary AVM in HHT1 mutation carriers who are ENG haploinsufficient. Genetic association was found between rs10987746 of the wild type ENG allele and presence of pulmonary AVM [relative risk = 1.3 (1.0018–1.7424)]. The rs10987746-C at-risk allele associated with lower expression of ENG RNA in a panel of human lymphoblastoid cell lines (P = 0.004). Moreover, in angiogenically active human lung adenocarcinoma tissue, but not in uninvolved quiescent lung, rs10987746-C was correlated with expression of PTPN14 (P = 0.004), another modifier of HHT. Quantitative TAQMAN expression analysis in a panel of normal lung tissues from 69 genetically heterogeneous inter-specific backcross mice, demonstrated strong correlation between expression levels of Eng, Acvrl1, and Ptpn14 (r2 = 0.75–0.9, P < 1 × 10−12), further suggesting a direct or indirect interaction between these three genes in lung in vivo. Our data indicate that genetic variation within the single functional ENG gene influences quantitative and/or qualitative differences in ENG expression that contribute to risk of pulmonary AVM in HHT1, and provide correlative support for PTPN14 involvement in endoglin/ALK1 lung biology in vivo. PTPN14 has been shown to be a negative regulator of Yap/Taz signaling, which is implicated in mechanotransduction, providing a possible molecular link between endoglin/ALK1 signaling and mechanical stress. EMILIN2, which showed suggestive genetic association with pulmonary AVM, is also reported to interact with Taz in angiogenesis. Elucidation of the molecular mechanisms regulating these interactions in endothelial cells may ultimately provide more rational choices for HHT therapy.

Highlights

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder resulting from loss of function mutations predominantly in ENG (HHT type 1) or ACVRL1 aka ALK1 (HHT type 2) (Shovlin, 2010; Faughnan et al, 2011)
In the Dutch HHT cohort, primarily within HHT1, we found evidence of suggestive genetic association between the prevalence of pulmonary arteriovenous malformations (AVMs) in three out of seven tagSNPs spanning the HHT1 causative gene, ENG (P = 5.4 × 10−3 for the intronic SNP rs10987746 in HHT1; Gamete Competition (GC) test, Supplementary Table S2), and a similar observation was made within the French HHT1 population
We tested for genetic association between rs10987746 within the wild type ENG allele and the prevalence of pulmonary AVMs in Dutch HHT1, and confirmed the notion that genetic variation within the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary AVM in HHT1 (rs10987746-C relative risk = 1.3 (1.0018–1.7424) (Table 1)

Summary

Introduction

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder resulting from loss of function mutations predominantly in ENG (HHT type 1) or ACVRL1 aka ALK1 (HHT type 2) (Shovlin, 2010; Faughnan et al, 2011). These genes encode cell surface receptors which are components of the TGF-β/BMP signal transduction pathways active predominantly in endothelial cells. HHT is highly penetrant, but with age dependent expression of different clinical features (Shovlin, 2010; Faughnan et al, 2011)

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Conclusion