講演情報
[OE3-3]Camurati-Engelmann病II型の疾患遺伝子の同定
○王 錚1, 西村 玄1, 三宅 紀子2, 米谷 充弘3, 吉浦 孝一郎4, 今村 健志5, 大橋 博文6, 戸口田 淳也7, 松本 直通2, 池川 志郎1 (1.理化学研究所 生命医科学研究センター, 2.横浜市立大学医学部, 3.金沢大学医薬保健学総合研究科, 4.長崎大学大学院医歯薬学総合研究科, 5.愛媛大学医学部, 6.埼玉県立小児医療センター, 7.京都大学ウイルス・再生医科学研究所)
Camurati-Engelmann disease (CED) is a rare skeletal disease featured by progressive hyperostosis of the skull base and the diaphyses of the long tubular bones. CED is clinically and genetically heterogeneous. In some patients, transforming growth factor beta-1 (TGFB1) was identified as their disease gene and they were classified as CED type I (CED1). However, in many CED patients, no TGFB1 mutation was identified and they showed a different pattern of hyperostosis classified as CED type II (CED2). In this study, we explored the disease gene for CED2 and its pathogenic mechanism . We recruited three unrelated CED2 pedigrees of various ethnic backgrounds. By exome sequencing, we identified heterozygous in-frame deletion or missense variants in TGFB2 in the pedigrees. The variants identified in the three CED2 patients occurred de novo and were located in the “straitjacket” subdomain at the N-terminal of the latency-associated protein domain of TGFB2. By in vitro assays for the TGFB-SMAD signal, we confirmed that the CED2-related variants were gain-of-function mutations. The CED2 patient-derived MSCs showed significantly accelerated osteoblastic differentiation compared to those from the normal individuals. The pattern of hyperostosis in patients with the TGFB2 mutations was different from that in CED1 patients, indicating similar but distinctive functions of TGFB1 and TGFB2. Our results would facilitate the genetic diagnosis of CED and provide a clue for understanding the distinctive function of TGFBs in osteogenesis.