Role of X Gene Variant in Childhood Pulmonary Arterial Hypertension

Research Project

Project/Area Number	15K19639
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Pediatrics
Research Institution	Tokyo Women's Medical University
Principal Investigator	Nagai Ayako 東京女子医科大学, 医学部, 研究生 (10622160)
Research Collaborator	NAKANISHI Toshio FURUTANI Yoshiyuki
Project Period (FY)	2015-04-01 – 2018-03-31
Project Status	Completed (Fiscal Year 2017)
Budget Amount *help	¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000) Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords	肺動脈性肺高血圧症 / 遺伝子変異
Outline of Final Research Achievements	In order to find novel disease-causing variants in patients with pulmonary arterial hypertension, we performed direct sequencing and multiplex ligation-dependent probe amplification to analyze 18 families with multiple affected family members with PAH. In one of the 18 families with PAH, there were no disease-causing variants already-known. Whole-exome next-generation sequencing was performed in the family, and we identified a novel variant in X gene in the family. The variant, R554L-X, revealed gain-of-function and induced decreasing nucleus p53 and p21, lower phosphorylation of nucleus p53, decreasing apoptotic hPASMCs, and increasing hPASMCs proliferation and cell viability compared to wild-type X. This study can contribute to elucidate mechanism of PAH pathogenesis.