Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.
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.
Pandit
Bhaswati
B
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.
Sarkozy
Anna
A
Pennacchio
Len A
LA
Carta
Claudio
C
Oishi
Kimihiko
K
Martinelli
Simone
S
Pogna
Edgar A
EA
Schackwitz
Wendy
W
Ustaszewska
Anna
A
Landstrom
Andrew
A
Bos
J Martijn
JM
Ommen
Steve R
SR
Esposito
Giorgia
G
Lepri
Francesca
F
Faul
Christian
C
Mundel
Peter
P
López Siguero
Juan P
JP
Tenconi
Romano
R
Selicorni
Angelo
A
Rossi
Cesare
C
Mazzanti
Laura
L
Torrente
Isabella
I
Marino
Bruno
B
Digilio
Maria C
MC
Zampino
Giuseppe
G
Ackerman
Michael J
MJ
Dallapiccola
Bruno
B
Tartaglia
Marco
M
Gelb
Bruce D
BD
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
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