@article{e7a4609851834b55b092d9201d42e230,
title = "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy",
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 ∼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.",
author = "Bhaswati Pandit and Anna Sarkozy and Pennacchio, {Len A.} and Claudio Carta and Kimihiko Oishi and Simone Martinelli and Pogna, {Edgar A.} and Wendy Schackwitz and Anna Ustaszewska and Andrew Landstrom and Bos, {J. Martijn} and Ommen, {Steve R.} and Giorgia Esposito and Francesca Lepri and Christian Faul and Peter Mundel and {L{\'o}pez Siguero}, {Juan P.} and Romano Tenconi and Angelo Selicorni and Cesare Rossi and Laura Mazzanti and Isabella Torrente and Bruno Marino and Digilio, {Maria C.} and Giuseppe Zampino and Ackerman, {Michael J.} and Bruno Dallapiccola and Marco Tartaglia and Gelb, {Bruce D.}",
note = "Funding Information: We are indebted to the affected individuals and families who participated in the study, the physicians who referred the subjects and the Joint Genome Institute{\textquoteright}s production sequencing group. We thank D.K. Morrison (National Cancer Institute, US National Institutes of Health) for critical reagents and suggestions. We also thank G. Crisponi (Clinica Sant{\textquoteright}Anna, Cagliari, Italy), F. Faravelli (Ospedale Galliera, Genova, Italy), L. Memo (ULLS9, Treviso, Italy) and F. Stanzial (Regional Hospital, Bolzano, Italy) for their valuable clinical assistance. This work was supported by Telethon-Italy grant GGP07115 (M.T.) and Programma di Collaborazione Italia-USA/malattie rare 2007 grants (M.T. and A.S.); US National Institutes of Health Grants HL71207, HD01294, HL074728 (B.D.G.), HD042569 (M.J.A.) and DK57683 (P.M.); the American Heart Association (M.J.A.); the Dr. Scholl Foundation (M.J.A.); the CJ Foundation for SIDS and the Mayo Foundation (M.J.A.) and Italian Ministry of Health Grant RC 2006-2007, Italian Ministry of University and Research C26A06KTTN and RBIP06PMF2_005 (B.D.). Research conducted at the E.O. Lawrence Berkeley National Laboratory and the Joint Genome Institute was performed under the Berkeley Program for Genomic Applications, funded by the US National Heart, Lung and Blood Institute (HL066681) and Department of Energy Contract DE-AC02-05CH11231 (University of California). We regret our inability to cite certain references describing work similar to references that were cited due to the limits of this journal.",
year = "2007",
month = aug,
doi = "10.1038/ng2073",
language = "English (US)",
volume = "39",
pages = "1007--1012",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "8",
}