2. Academic Validation
  3. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy

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

  • Nat Genet. 2007 Aug;39(8):1007-12. doi: 10.1038/ng2073.
Bhaswati Pandit 1,  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 Rossi,  Laura Mazzanti,  Isabella Torrente,  Bruno Marino,  Maria C Digilio,  Giuseppe Zampino,  Michael J Ackerman,  Bruno Dallapiccola,  Marco Tartaglia,  Bruce D Gelb
Affiliations

Affiliation

  • 1 Center for Molecular Cardiology, Department of Pediatrics and Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
PMID: 17603483 DOI: 10.1038/ng2073
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 approximately 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.

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