Molecular mechanism of myocardial hypertrophy caused by PTPN11 mutation in Noonan's syndrome

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15910
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Keio University
• Principal Investigator: Ishizaki Reina 慶應義塾大学, 医学部(信濃町), 助教 (70528299)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Noonan症候群 / 肥大型心筋症 / PTPN11

Outline of Final Research Achievements

It remains to be elucidated the mechanism how secondary cardiomyopathy develops in some cases of Noonan syndrome. We focused on two mutants in the Noonan syndrome causative gene, PTPN11, the mutant X, which has not been reported to cause cardiomyopathy, and the mutant Y, which was detected in our case with secondary cardiomyopathy. cDNAs of the mutant X and Y, and wild type human PTPN11 were overexpressed in neonatal rat cardiomyocytes (NRCM) using adenoviral vectors and the phenotypes of NRCMs were compared at the cellular level. NRCM overexpressing two mutants showed disrupted sarcomere architecture. And NRCMs overexpressing Y exhibited downregulation of cell size and also decreased survival numbers. These results suggest that the mutant Y of human PTPN11 might contribute to the maintenance of cell architecture and cell survival in NRCM.

Free Research Field

心臓発生

Academic Significance and Societal Importance of the Research Achievements

Noonan症候群は、1000-2500人に1人の割合で発症する常染色体優性遺伝病である。80％に心血管疾患を合併し、そのうち約20%に心筋肥大を示す二次性心筋症を認める。二次性心筋症については、疾患関連遺伝子変異のうちRAF1変異で重症例が多く認められる一方、PTPN11変異では頻度は低く、重症度も様々である。本研究では、遺伝子型表現型相関について解析が進んでいるRAF1変異例と比較して未解明な点の多いPTPN11変異例において、二次性心筋症が発症する分子メカニズムを解明することにより、二次性心筋症の重症化の機序を明らかにし、疾患特異的治療の一助にする事を目的とした。