Abstract for presentation at 11th International Congress of Human Genetics

Cardio-facio-cutaneous (CFC) syndrome is characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities, and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome. The molecular basis of this disorder has remained unknown. Recently, we identified germline mutations in HRAS in individuals with Costello syndrome. This finding led us to examine RAS family genes and the downstream molecules of RAS in the signaling pathway in 43 patients with CFC syndrome. In three of these affected individuals, we identified two de novo heterozygous mutations located in highly conserved regions of KRAS. In sixteen affected individuals we identified eight heterozygous mutations in BRAF, one of the RAF kinases, these kinases being regulated by binding RAS. Six of these eight BRAF mutations were identified in eleven individuals. These six mutations are located in a catalytic cleft of the kinase domain, where somatic substitutions have been observed in cancers, including melanoma. The other two mutations, located in the cysteine-rich domain, were identified in five individuals. These results showed that KRAS or BRAF mutations account for 44 % of patients with CFC syndrome. No mutations in HRAS, NRAS, KRAS and BRAF were found in 24 affected individuals, suggesting further genetic heterogeneity of the disorder. Luciferase assays to assess activation downstream of ERK (extracellular signal regulated kinase) showed that one KRAS mutation and five BRAF mutations stimulated ELK1-dependent transcription. Our results suggest that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for Noonan syndrome, Costello syndrome and CFC syndrome.
Niihori et al. Nature Genetics, in press.