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


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.

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Figure 1: Mutations in RAF1 were identified in individuals with Noonan syndrome.
Figure 2: Functional characterization of RAF1 mutants identified in Noonan syndrome.
Figure 3: Detection of heart malformation by knockdown of raf1 and ptpn11 in zebrafish.

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The authors are grateful to the patients, their family members and the referring physicians. We thank B. Nadal-Ginard for his critical reading of the manuscript and for discussions. We also thank S. Arai and S. Imamura for generating Epstein-Barr virus–transformed lymphoblastoid cell lines of the subjects; K. Hirayama-Yamada, K. Komatsu, H. Nagao and K. Kihara for technical assistance and B. Levene for English correction of the manuscript. H.Y. was supported by a research fellowship from the Japan Society for the Promotion of Science. This project was supported by the Encouraging Development of Strategic Research Centers, Special Coordination Funds for Promoting Science and Technology, Ministry of Education, Culture, Sports, Science and Technology, Japan.

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M.A.R. and R.M. designed experiments; M.A.R. performed sequencing and biochemical analysis; plasmid construction was done by M.A.R., T.N. and H.Y.; patient phenotyping was performed by M.F., M.K., K.M., H.K., M.N., Y.F., M.M., K.M., M.T., H.H., J.M. and R.M.; zebrafish experiments were contributed by Y.K., R.A. and T.H.; M.A.R. and R.M. wrote the paper and R.M. organized and supervised the project.

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Correspondence to Rumiko Matsuoka.

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The authors declare no competing financial interests.

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Supplementary Figs 1-3, Supplementary Tables 1-2, Supp Methods (PDF 377 kb)

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Razzaque, M., Nishizawa, T., Komoike, Y. et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 39, 1013–1017 (2007).

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