title: Germline gain-of-function mutations in RAF1 cause Noonan syndrome.
abstract: 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 approximately 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.
authors.affiliation: International Research and Educational Institute for Integrated Medical Sciences (IREIIMS), Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: M Abdur
authors.initials: MA
authors.lastname: Razzaque
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishizawa
authors.forename: Yuta
authors.initials: Y
authors.lastname: Komoike
authors.forename: Hisato
authors.initials: H
authors.lastname: Yagi
authors.forename: Michiko
authors.initials: M
authors.lastname: Furutani
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Amo
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kamisago
authors.forename: Kazuo
authors.initials: K
authors.lastname: Momma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katayama
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsushima
authors.forename: Katsumi
authors.initials: K
authors.lastname: Mizuno
authors.forename: Mika
authors.initials: M
authors.lastname: Tokuyama
authors.forename: Hamao
authors.initials: H
authors.lastname: Hirota
authors.forename: Jun
authors.initials: J
authors.lastname: Muneuchi
authors.forename: Toru
authors.initials: T
authors.lastname: Higashinakagawa
authors.forename: Rumiko
authors.initials: R
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D005260:Female; D006321:Heart / Q000196:embryology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D009634:Noonan Syndrome / Q000235:genetics*; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D029961:Zebrafish Proteins; D019908:Proto-Oncogene Proteins c-raf; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases