Germline gain-of-function mutations in RAF1 cause Noonan syndrome

• Published in: Nature genetics Vol. 39; no. 8; pp. 1013 - 1017
• Main Authors: Nishizawa, Tsutomu, Amo, Ryunosuke, Komoike, Yuta, Hirota, Hamao, Fujiwara, Yuko, Higashinakagawa, Toru, Katayama, Hiroshi, Razzaque, M Abdur, Furutani, Michiko, Momma, Kazuo, Muneuchi, Jun, Yagi, Hisato, Nakagawa, Masao, Mizuno, Katsumi, Tokuyama, Mika, Kamisago, Mitsuhiro, Matsuoka, Rumiko, Matsushima, Masaki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-08-2007
• Subjects: Animals; Biological and medical sciences; Causes of; Cell Line; Cell Line, Transformed; Cellular biology; Cellular signal transduction; Complications and side effects; Danio rerio; Developmental disabilities; Diseases of the osteoarticular system; Embryos; Female; Freshwater; Fundamental and applied biological sciences. Psychology; Gene expression; Gene mutations; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Heart - embryology; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mutation; Mutation, Missense; Myocardium - metabolism; Noonan syndrome; Noonan Syndrome - genetics; Physiological aspects; Protein Structure, Tertiary; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Proto-Oncogene Proteins c-raf - chemistry; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; Japan; Nervous system diseases; Germ line; Noonan syndrome; Diseases of the osteoarticular system; Cardiovascular disease; Mutation; Osteochondrodysplasia; Genetic disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng2078

Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause ∼60% of cases of Noonan syndrome. 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.