PUBLICATION
Germline gain-of-function mutations in RAF1 cause Noonan syndrome
- Authors
- Razzaque, M.A., Nishizawa, T., Komoike, Y., Yagi, H., Furutani, M., Amo, R., Kamisago, M., Momma, K., Katayama, H., Nakagawa, M., Fujiwara, Y., Matsushima, M., Mizuno, K., Tokuyama, M., Hirota, H., Muneuchi, J., Higashinakagawa, T., and Matsuoka, R.
- ID
- ZDB-PUB-070711-24
- Date
- 2007
- Source
- Nature Genetics 39(8): 1013-1017 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line
- Cell Line, Transformed
- Female
- Heart/embryology
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Mutation, Missense*
- Myocardium/metabolism
- Noonan Syndrome/genetics*
- 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
- PubMed
- 17603482 Full text @ Nat. Genet.
Citation
Razzaque, M.A., Nishizawa, T., Komoike, Y., Yagi, H., Furutani, M., Amo, R., Kamisago, M., Momma, K., Katayama, H., Nakagawa, M., Fujiwara, Y., Matsushima, M., Mizuno, K., Tokuyama, M., Hirota, H., Muneuchi, J., Higashinakagawa, T., and Matsuoka, R. (2007) Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nature Genetics. 39(8):1013-1017.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping