Comprehensive genetic analysis of Noonan syndrome and related disorders using next-generation sequencing(Fostering Joint International Research)

2018 Fiscal Year Final Research Report

• Project/Area Number: 15KK0293
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: Niihori Tetsuya 東北大学, 医学系研究科, 准教授 (40436134)
• Research Collaborator: Katsanis Nicholas Duke University Medical Center, Center for Human Disease Modeling, Professor ; Aoki Yoko ; Nagai Koki ; Davis Erica E.
• Project Period (FY): 2016 – 2018
• Keywords: ヌーナン症候群 / ゼブラフィッシュ

Outline of Final Research Achievements

We identified RRAS2 variants in patients with Noonan syndrome. We injected the wild-type or variant RNAs of RRAS2 into 1-4 cell-stage embryos. We measured the ceratohyal angle and body length of the larvae at 3 days post fertilization. The ceratohyal angles of larvae introduced with the variants were greater than that of wild-type. The body lengths of larvae with the variants were shorter than that of wild-type. These observations support the hypothesis that RRAS2 is a novel responsible gene of Noonan syndrome.

Free Research Field

臨床遺伝学

Academic Significance and Societal Importance of the Research Achievements

本研究はRRAS2の変異が先天性疾患であるヌーナン症候群の原因になることを世界で初めて明らかにするものである。ヌーナン症候群は指定難病および小児慢性特定疾病であり、診断基準上の「確実なヌーナン症候群」の診断は臨床症状より行われるが、判断が困難な場合がありうる。一方で「確定診断されたヌーナン症候群」は「上記確実なヌーナン症候群の要件を満たし、PTPN11などのRAS/MAPKシグナル伝達経路のヌーナン症候群責任遺伝子群に変異が同定された場合」とされており、RRAS2はヌーナン症候群責任遺伝子群の1つと考えられる。そのため、この発見は指定難病・小児慢性特定疾病と確定診断するために重要である。