A Genetic Analysis for Patients with Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a lethal disease [1]. Although mutations in BMPR2 and other genes have been reported, the genetic causes in large numbers of patients, especially with sporadic PAH, remain unknown. In 2013, Kerstjens-Frederikse et al. first reported TBX4 mutations in patients with PAH [2]. TBX4 is an essential transcription factor for the development of the hindlimbs and lungs [3]. In European countries, the frequency of TBX4 mutation was reported as 2.4–4.1% in adult-onset PAH [2, 4] and as 7.5–30% in child-onset PAH [2, 5] (Fig. 27.1). However, its frequency in Asian patients with PAH has yet to be studied.

Pulmonary arterial hypertension (PAH) is a lethal disease [1]. Although mutations in BMPR2 and other genes have been reported, the genetic causes in large numbers of patients, especially with sporadic PAH, remain unknown. In 2013, Kerstjens-Frederikse et al. first reported TBX4 mutations in patients with PAH [2]. TBX4 is an essential transcription factor for the development of the hindlimbs and lungs [3]. In European countries, the frequency of TBX4 mutation was reported as 2.4–4.1% in adult-onset PAH [2, 4] and as 7.5–30% in child-onset PAH [2, 5] (Fig. 27.1). However, its frequency in Asian patients with PAH has yet to be studied.

Fig. 27.1

Summary of the position of the previously reported variants in TBX4. Upper labels indicate variants with child-onset PAH; lower labels indicate variants with adult-onset PAH. NLS nuclear localization signal

In our genetic analysis for patients with PAH, at least nine sequence variants in exons and six sequence variants in flanking introns of TBX4 were found. The allele frequencies of variants in the Japanese population are under investigation. The detected variants will be validated using the following web databases: UCSC genome browser (https://genome-asia.ucsc.edu), Ensembl (http://www.ensembl.org), PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2), SIFT (http://sift.jcvi.org), Human Splicing Finder (http://umd.be/HSF3), and Protein Data Bank Japan (https://pdbj.org) for their functional significance. We are further attempting to establish the experimental system of functional analysis for the identified variants of TBX4 using cell culture with luciferase, immunoprecipitation, and immunohistochemistry assays in order to elucidate the molecular mechanism underlying PAH resulting from TBX4 mutations.

This study suggests that TBX4 may be a prevalent genetic cause of PAH not only in Caucasians but also within Japanese/Asian populations. Our ongoing studies would soon reveal the functional relevance and genotype–phenotype correlations in patients with PAH associated with TBX4 mutations.