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 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.
authors.affiliation: 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.
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Pandit
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Claudio
authors.initials: C
authors.lastname: Carta
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Oishi
authors.forename: Simone
authors.initials: S
authors.lastname: Martinelli
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Pogna
authors.forename: Wendy
authors.initials: W
authors.lastname: Schackwitz
authors.forename: Anna
authors.initials: A
authors.lastname: Ustaszewska
authors.forename: Andrew
authors.initials: A
authors.lastname: Landstrom
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.forename: Steve R
authors.initials: SR
authors.lastname: Ommen
authors.forename: Giorgia
authors.initials: G
authors.lastname: Esposito
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
authors.forename: Juan P
authors.initials: JP
authors.lastname: López Siguero
authors.forename: Romano
authors.initials: R
authors.lastname: Tenconi
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Cesare
authors.initials: C
authors.lastname: Rossi
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.forename: Isabella
authors.initials: I
authors.lastname: Torrente
authors.forename: Bruno
authors.initials: B
authors.lastname: Marino
authors.forename: Maria C
authors.initials: MC
authors.lastname: Digilio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D000818:Animals; D019556:COS Cells; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D044542:LEOPARD Syndrome / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D019908:Proto-Oncogene Proteins c-raf; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D018631:ras Proteins