Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension

Chida-Nagai, Ayako, Shintani, Masaki, Sato, Hiroki, Nakayama, Tomotaka, Nii, Masaki, Akagawa, Hiroyuki, Furukawa, Toru, Rana, Amer ORCID:, Furutani, Yoshiyuki, Inai, Kei, Nonoyama, Shigeaki and Nakanishi, Toshio (2019) Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension. PLoS One, 14 (1). ISSN 1932-6203

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Although mutations in several genes have been reported in pulmonary arterial hypertension (PAH), most of PAH cases do not carry these mutations. This study aimed to identify a novel cause of PAH. To determine the disease-causing variants, direct sequencing and multiplex ligation-dependent probe amplification were performed to analyze 18 families with multiple affected family members with PAH. In one of the 18 families with PAH, no disease-causing variants were found in any of BMPR2, ACVRL1, ENG, SMAD1/4/8, BMPR1B, NOTCH3, CAV1, or KCNK3. In this family, a female proband and her paternal aunt developed PAH in their childhood. Whole-exome next-generation sequencing was performed in the 2 PAH patients and the proband's healthy mother, and a BRCA1-associated protein (BRAP) gene variant, p.Arg554Leu, was identified in the 2 family members with PAH, but not in the proband's mother without PAH. Functional analyses were performed using human pulmonary arterial smooth muscle cells (hPASMCs). Knockdown of BRAP via small interfering RNA in hPASMCs induced p53 signaling pathway activation and decreased cell proliferation. Overexpression of either wild-type BRAP or p.Arg554Leu-BRAP cDNA constructs caused cell death confounding these studies, however we observed higher levels of p53 signaling inactivation and hPASMC proliferation in cells expressing p.Arg554Leu-BRAP compared to wild-type BRAP. In addition, p. Arg554Leu-BRAP induced decreased apoptosis of hPASMCs compared with wild-type BRAP. In conclusion, we have identified a novel variant of BRAP in a Japanese family with PAH and our results suggest it could have a gain-of-function. This study sheds light on new mechanism of PAH pathogenesis.

Item Type: Article
Additional Information: Funding Information: This work was supported by MEXT KAKENHI Grant Number 15K19639 (http://www. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2019 Chida-Nagai et al.
Uncontrolled Keywords: general,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 01 Nov 2022 14:31
Last Modified: 07 Nov 2022 00:49
DOI: 10.1371/journal.pone.0211450

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