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 similar to 60% of Noonan syndrome cases(1-6), and PTPN11 mutations cause 90% of LEOPARD syndrome cases7. 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.
Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy / Bhaswati, Pandit; Anna, Sarkozy; Len A., Pennacchio; Claudio, Carta; Kimihiko, Oishi; Simone, Martinelli; Edgar A., Pogna; Wendy, Schackwitz; Anna, Ustaszewska; Andrew, Landstrom; J., Martijn Bos; Steve R., Ommen; Giorgia, Esposito; Francesca, Lepri; Christian, Faul; Peter, Mundel; Juan P., Lopez Siguero; Romano, Tenconi; Angelo, Selicorni; Cesare, Rossi; Laura, Mazzanti; Isabella, Torrente; MARINO TAUSSIG DE BODONIA, Bruno; Maria C., Digilio; Giuseppe, Zampino; Michael J., Ackerman; DALLA PICCOLA, Bruno; Marco, Tartaglia; Bruce D., Gelb. - In: NATURE GENETICS. - ISSN 1061-4036. - 39:8(2007), pp. 1007-1012. [10.1038/ng2073]
Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy
MARINO TAUSSIG DE BODONIA, Bruno;DALLA PICCOLA, Bruno;
2007
Abstract
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 similar to 60% of Noonan syndrome cases(1-6), and PTPN11 mutations cause 90% of LEOPARD syndrome cases7. 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
