フルタニ　ヨシユキ   Furutani Yoshiyuki   古谷　喜幸    所属   医学部 医学科（東京女子医科大学病院）    職種   非常勤講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension.
掲載誌名	正式名：PloS one 略　 称：PLoS One ISSNコード：19326203
掲載区分	国外
出版社	Public Library of Science (PLOS)
巻・号・頁	14(1),pp.e0211450
著者・共著者	CHIDA-NAGAI Ayako†, SHINTANI Masaki, SATO Hiroki, NAKAYAMA Tomotaka, NII Masaki, AKAGAWA Hiroyuki, FURUKAWA Toru, AMER Rana, FURUTANI Yoshiyuki, INAI Kei, NONOYAMA Shigeaki, NAKANISHI Toshio*
発行年月	2019/01
概要	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.
DOI	10.1371/journal.pone.0211450
PMID	30703135