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: M Abdur Razzaque, Tsutomu Nishizawa, Yuta Komoike, Hisato Yagi, Michiko Furutani, Ryunosuke Amo, Mitsuhiro Kamisago, Kazuo Momma, Hiroshi Katayama, Masao Nakagawa, Yuko Fujiwara, Masaki Matsushima, Katsumi Mizuno, Mika Tokuyama, Hamao Hirota, Jun Muneuchi, Toru Higashinakagawa, Rumiko Matsuoka
• Journal: Nature genetics (Nat Genet) Vol. 39 Issue 8 Pg. 1013-7 (Aug 2007) ISSN: 1061-4036 [Print] United States
• PMID: 17603482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Zebrafish Proteins
• Proto-Oncogene Proteins c-raf
• PTPN11 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Protein Tyrosine Phosphatases

Topics

• Animals
• Cell Line
• Cell Line, Transformed
• Female
• Heart (embryology)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Mutation, Missense
• Myocardium (metabolism)
• Noonan Syndrome (genetics)
• Protein Structure, Tertiary
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Protein Tyrosine Phosphatases (genetics, metabolism)
• Proto-Oncogene Proteins c-raf (chemistry, genetics, metabolism)
• Zebrafish
• Zebrafish Proteins (genetics, metabolism)