Genetic analysis of Primary Pulmonary Hypertension and possible involvement of Tbx genes via BMP signaling in the pathogenesis of PPH.

• Project/Area Number: 16590265
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: MORISAKI Hiroko National Cardiovascular Center Research Institute, Department of Bioscience, Laboratory Chief, バイオサイエンス部, 室長 (40311451)
• Co-Investigator(Kenkyū-buntansha): MORISAKI Takayuki National Cardiovascular Center Research Institute, Department of Bioscience, Director, バイオサイエンス部, 部長 (30174410) ; SHIRAI Manabu National Cardiovascular Center Research Institute, Department of Bioscience, Research Staff, バイオサイエンス部, 室員 (70294121)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,000,000 (Direct Cost: ¥3,000,000); Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: Primary Plumonary Hypertension / Genetic Analysis / BMPR2 / ALK1 / BMP / Tbx2 / Has2 / 原発性高血圧症

Research Abstract

1. Primary pulmonary hypertension (PPH) is a potentially lethal disorder, in which heterozygous mutations within the bone morphogenetic protein type II receptor gene (BMPR2) have been identified. We performed the molecular study of BMPR2 gene as well as ALK1 gene in 71 Japanese patients with PPH including 7 familial PPH cases (6 families), who visited the Division of Cardiology in NCVC. We also performed the molecular study in 64 cases with secondary pulmonary hypertension (SPH). We identified mutations of BMPR2 gene in 27 cases (38%) of patients with PPH, including all familial PPH cases, while only one patient with SPH was found to have BMPR2 mutation. Furthermore, three cases (4%) of patients with PPH and one with SPH were found to have ALK1 mutations. Those mutations are predicted to result in a premature termination codon or substitution of highly conserved amino acid residues. We also analyzed the age of onset among sporadic PPH patients according to genetic background. The mean age at onset was significantly younger in those with mutations than those without mutations, suggesting a considerable genetic predisposition underlying the pathogenesis of PPH. Furthermore, genetic analysis of family members of familial PPH revealed a very low penetrance (1 in 8 affected was eventually developed PPH) Based on these results, there is considerable genetic heterogeneity of PPH, and further functional study will be needed to identify pathophysiological mechanism of pulmonary hypertension.
2. We demonstrate that Tbx2 is important for cardiac morphogenesis by using inducible mTbx2-misexpression mice. The mTbx2-overexpressing mice showed the changes of chamber-specific gene expression of Nppa, Smpx, Gja5,Myh7 and Myl7 at E9.5 and E9.75. In addition, we found the expression of Hyaluronan Synthase 2 (Has2) was upregulated in the ventricles during cardiogenesis. Also, we observed excessive HA secretion in the ventricular myocytes of mTbx2-misexpressing embryos.

Research Products

• [Journal Article] Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. (2006)
  • Author(s): Machado RD, Aldred MA, James V, et al.
  • Journal Title: Human Mutation 27 Pages: 121-132
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. (2006)
  • Author(s): Machado RD, Aldred MA, James V, et al.
  • Journal Title: Human Mutation Vol.27(2) Pages: 121-132
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. (2006)
  • Author(s): Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, Eickelberg O, Olschewski H, Elliott CG, Glissmeyer E, Carlquist J, Kim M, Torbicki A, Fijalkowska A, Szewczyk G, Parma J, Abramowicz MJ, Galie N, Morisaki H, Kyotani S, Nakanishi N, Morisaki T, Humbert M, Simonneau G, Sitbon O, Soubrier F, Coulet F, Morrell NW, Trembath RC.
  • Journal Title: Human Mutation 27 Pages: 121-132
• [Journal Article] BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. (2004)
  • Author(s): Morisaki H, Nakanishi N, Kyotani S, et al.
  • Journal Title: Human Mutation 23 Pages: 632-632
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. (2004)
  • Author(s): Morisaki H, Nakanishi N, Kyotani S, et al.
  • Journal Title: Human Mutation Vol.23(6) Pages: 632-632
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. (2004)
  • Author(s): Morisaki H, Nakanishi N, Kyotani S, Takashima A, Tomoike H, Morisaki T
  • Journal Title: Human Mutation 6 Pages: 632-632
• [Book] Heart View : 肺高血圧症を診る (2006)
  • Author(s): 森崎裕子
  • Total Pages: 4
  • Publisher: メディカルビュー社
  • Description: 「研究成果報告書概要(和文)」より