Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy

• Published in: Nature genetics Vol. 39; no. 8; pp. 1007 - 1012
• Main Authors: Sarkozy, Anna, López Siguero, Juan P, Tartaglia, Marco, Ackerman, Michael J, Rossi, Cesare, Digilio, Maria C, Mundel, Peter, Torrente, Isabella, Tenconi, Romano, Mazzanti, Laura, Selicorni, Angelo, Landstrom, Andrew, Marino, Bruno, Bos, J Martijn, Pogna, Edgar A, Oishi, Kimihiko, Gelb, Bruce D, Martinelli, Simone, Schackwitz, Wendy, Pennacchio, Len A, Carta, Claudio, Pandit, Bhaswati, Ustaszewska, Anna, Zampino, Giuseppe, Ommen, Steve R, Dallapiccola, Bruno, Esposito, Giorgia, Lepri, Francesca, Faul, Christian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.08.2007
• Subjects: Animals; Binding sites; Biological and medical sciences; Cardiomyopathy, Hypertrophic; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - metabolism; Cardiovascular disease; Chlorocebus aethiops; Complex syndromes; Complications and side effects; COS Cells; Developmental disabilities; Diagnosis; Diseases of the osteoarticular system; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; Intracellular Signaling Peptides and Proteins - genetics; LEOPARD Syndrome - genetics; LEOPARD Syndrome - metabolism; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical genetics; Medical sciences; Mutation; Mutation, Missense; Noonan syndrome; Noonan Syndrome - genetics; Noonan Syndrome - metabolism; Protein Structure, Tertiary; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases - genetics; Proto-Oncogene Proteins c-raf - chemistry; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; ras Proteins - metabolism; Risk factors; Signal Transduction; Transfection; Italy; Nervous system diseases; Diseases of the osteoarticular system; Cardiovascular disease; Myocardial disease; Genital diseases; Genetic disease; Heart disease; Noonan syndrome; Hypertrophic cardiomyopathy; ENT disease; Mutation; Osteochondrodysplasia; LEOPARD syndrome
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng2073

Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes ∼60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.