Letter abstract
Nature Genetics 39, 1013 - 1017 (2007)
Published online: 1 July 2007 | doi:10.1038/ng2078
Germline gain-of-function mutations in RAF1 cause Noonan syndrome
M Abdur Razzaque1, Tsutomu Nishizawa1, Yuta Komoike1,2, Hisato Yagi1,3, Michiko Furutani1,4, Ryunosuke Amo1,2, Mitsuhiro Kamisago4, Kazuo Momma4, Hiroshi Katayama5, Masao Nakagawa6, Yuko Fujiwara7, Masaki Matsushima8, Katsumi Mizuno9, Mika Tokuyama10, Hamao Hirota11, Jun Muneuchi12, Toru Higashinakagawa2 & Rumiko Matsuoka1,3,4
Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects1, 2. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause 
60% of cases of Noonan syndrome3, 4, 5, 6, 7, 8, 9. However, the gene(s) responsible for the remainder are unknown. We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome; those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas affected individuals with mutations leading to changes in the CR3 domain did not. Cells transfected with constructs containing Noonan syndrome–associated RAF1 mutations showed increased in vitro kinase and ERK activation, and zebrafish embryos with morpholino knockdown of raf1 demonstrated the need for raf1 for the development of normal myocardial structure and function. Thus, our findings implicate RAF1 gain-of-function mutations as a causative agent of a human developmental disorder, representing a new genetic mechanism for the activation of the MAPK pathway.
- International Research and Educational Institute for Integrated Medical Sciences (IREIIMS), Tokyo Women's Medical University, Tokyo 162-8666, Japan.
- Department of Biology, School of Education, Waseda University, Tokyo, Japan.
- Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo 162-8666, Japan.
- Division of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
- Department of Pediatrics, Osaka Medical College, Osaka, Japan.
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan.
- Department of Pediatrics, The Jikei University, Tokyo, Japan.
- Department of Pediatric Cardiology, Social Insurance Chukyo Hospital, Aichi, Japan.
- Department of Neonatology, Chiba Children's Hospital, Chiba, Japan.
- Department of Pediatrics, Toho University, Tokyo, Japan.
- Department of Pediatrics, Kitasato University, Kanagawa, Japan.
- Department of Pediatrics, Kyushu University, Fukuoka, Japan.
Correspondence to: Rumiko Matsuoka1,3,4 e-mail: rumiko@imcir.twmu.ac.jp
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