Online ISSN: 2187-2988 Print ISSN: 0911-1794
特定非営利活動法人日本小児循環器学会 Japanese Society of Pediatric Cardiology and Cardiac Surgery
Pediatric Cardiology and Cardiac Surgery 39(4): 192-199 (2023)


RASopathy心筋症病態理解の新たな展開Emerging Hypotheses on the Pathogenesis of Rasopathy-Associated Cardiomyopathies

1東京医科歯科大学 大学院医歯学総合研究科 循環制御内科学Department of Cardiovascular Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University ◇ Tokyo, Japan

2東京大学 大学院医学系研究科 循環器内科学Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo ◇ Tokyo, Japan

3東京大学 大学院医学系研究科 先端臨床医学開発講座Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, The University of Tokyo ◇ Tokyo, Japan

4大阪公立大学 大学院医学研究科 ウイルス・寄生虫学Department of Virology & Parasitology, Graduate School of Medicine, Osaka Metropolitan University ◇ Osaka, Japan

発行日:2023年12月31日Published: December 31, 2023

RAS/MAPK経路を構成する因子の過剰活性化は,RASopathyなる先天性疾患を引き起こし,心奇形,特異顔貌,骨格異常,知的障害といった多系統の組織に機能・形態異常を引き起こす.肥大型心筋症類似心肥大はRASopathyの特徴的な心臓表現型であり,その発症は心不全死および突然死リスクと強く相関する.RASopathy関連心筋症は小児循環器病学の重点疾患群であるが,その病態の全容は未だ明らかになっていない.特異的治療の臨床開発も滞っており,臨床医学と基礎研究の協奏による心臓ケアの質向上が,求められている.本総説では,RASopathy関連心筋症について基礎~早期臨床開発の現存するエビデンスを紹介しながら,今後,我々が埋めるべきナレッジ・ギャップを俯瞰する.さらに,RAS/MAPK経路異常を共通の分子病態にもつ「癌」と「RASopathy」の対比という視点から,RASopathy関連心筋症のcellular pathologyを再評価し,疾患特異的治療開発のヒントを探る.

RAS/mitogen activated protein kinase (MAPK) pathway dysregulation, triggered by germline mutations in the involved genes, leads to a congenital syndrome termed “RASopathy.” Each form of RASopathy expresses a unique clinical phenotype; however, they share a series of functional and morphological organ abnormalities, including cardiac malformations, specific facial features, skeletal abnormalities, and intellectual disabilities. Secondary hypertrophic cardiomyopathy is the characteristic cardiac phenotype of RASopathy; its presence is strongly associated with heart failure-related mortality and sudden death. Therefore, RASopathy-associated hypertrophic cardiomyopathy (RAS-CMP) is a disease of priority in pediatric cardiology. However, the complete picture of its pathogenesis remains to be elucidated. Along with the development of novel molecular therapeutics, improving the quality of RASopathy care through collaborations between basic research and clinical practice is significantly needed. This review aimed to introduce the current evidence surrounding RAS-CMP and outline the knowledge gaps that should be addressed. Moreover, from the viewpoint of biological analogies between RAS/MAPK-related cancers and RASopathies, we deepen our discussion of recently emerging clues for exploring novel therapeutic approaches to RASopathy care.

Key words: RASopathy; hypertrophic cardiomyopathy; RAS/mitogen-activated protein kinase signaling; Noonan syndrome

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