ORPHA: 648; DO: 0060583;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p25.2 | Noonan syndrome 5 | 611553 | Autosomal dominant | 3 | RAF1 | 164760 |
A number sign (#) is used with this entry because of evidence that Noonan syndrome-5 (NS5) is caused by heterozygous mutation in the RAF1 gene (164760) on chromosome 3p25.
For a phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).
Pandit et al. (2007) analyzed the RAF1 gene, a serine-threonine kinase that activates MEK1 (176872) and MEK2 (601263), in 231 individuals with Noonan syndrome who did not have mutations in the PTPN11 (176876), KRAS (190070), or SOS1 (182530) genes. They identified 13 different missense mutations in 18 unrelated patients with NS (see, e.g., 164760.0001-164760.0003); most mutations altered a motif flanking ser259 located in the CR2 domain. Of 17 Noonan patients with an RAF1 mutation in 2 hotspots, 16 (94%) had hypertrophic cardiomyopathy (CMH; see 192600), compared with an 18% prevalence of CMH among Noonan patients in general. Ectopically expressed RAF1 mutants from the 2 CMH hotspots had increased kinase activity and enhanced ERK (see 176948) activation, whereas non-CMH-associated mutants were kinase impaired.
Razzaque et al. (2007) analyzed the RAF1 gene in 30 individuals clinically diagnosed with Noonan syndrome who were negative for mutations in the PTPN11, KRAS, HRAS (190020), or SOS1 genes, and identified 5 different missense mutations in RAF1 in 10 (33%) individuals. The authors noted that those with any of 4 mutations causing changes in the CR2 domain of RAF1 (see, e.g., 164760.0001 and 164760.0003) had hypertrophic cardiomyopathy, whereas the 2 affected individuals with a mutation leading to changes in the CR3 domain did not (164760.0004).
Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., Pogna, E. A., Schackwitz, W., Ustaszewska, A., Landstrom, A., Bos, J. M., Ommen, S. R., and 17 others. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genet. 39: 1007-1012, 2007. [PubMed: 17603483] [Full Text: https://doi.org/10.1038/ng2073]
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., Matsuoka, R. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nature Genet. 39: 1013-1017, 2007. [PubMed: 17603482] [Full Text: https://doi.org/10.1038/ng2078]