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. López Siguero, Romano Tenconi, Angelo Selicorni, Cesare RossiLaura Mazzanti, Isabella Torrente, Bruno Marino, Maria C. Digilio, Giuseppe Zampino, Michael J. Ackerman, Bruno Dallapiccola, Marco Tartaglia, Bruce D. Gelb

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559 Scopus citations


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.

Original languageEnglish
Pages (from-to)1007-1012
Number of pages6
JournalNature Genetics
Issue number8
StatePublished - Aug 2007


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