TY - JOUR
T1 - Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy
AU - Pandit, Bhaswati
AU - Sarkozy, Anna
AU - Pennacchio, Len A.
AU - Carta, Claudio
AU - Oishi, Kimihiko
AU - Martinelli, Simone
AU - Pogna, Edgar A.
AU - Schackwitz, Wendy
AU - Ustaszewska, Anna
AU - Landstrom, Andrew
AU - Bos, J. Martijn
AU - Ommen, Steve R.
AU - Esposito, Giorgia
AU - Lepri, Francesca
AU - Faul, Christian
AU - Mundel, Peter
AU - López Siguero, Juan P.
AU - Tenconi, Romano
AU - Selicorni, Angelo
AU - Rossi, Cesare
AU - Mazzanti, Laura
AU - Torrente, Isabella
AU - Marino, Bruno
AU - Digilio, Maria C.
AU - Zampino, Giuseppe
AU - Ackerman, Michael J.
AU - Dallapiccola, Bruno
AU - Tartaglia, Marco
AU - Gelb, Bruce D.
PY - 2007/8
Y1 - 2007/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34547530823&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547530823&partnerID=8YFLogxK
U2 - 10.1038/ng2073
DO - 10.1038/ng2073
M3 - Article
C2 - 17603483
AN - SCOPUS:34547530823
VL - 39
SP - 1007
EP - 1012
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 8
ER -