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

Bhaswati Pandit, 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 H Faul, Peter Mundel, Juan P. López Siguero, Romano Tenconi, Angelo Selicorni, Cesare Rossi & 9 others Laura Mazzanti, Isabella Torrente, Bruno Marino, Maria C. Digilio, Giuseppe Zampino, Michael J. Ackerman, Bruno Dallapiccola, Marco Tartaglia, Bruce D. Gelb

Research output: Contribution to journalArticle

432 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1007-1012
Number of pages6
JournalNature Genetics
Volume39
Issue number8
DOIs
StatePublished - Aug 1 2007
Externally publishedYes

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LEOPARD Syndrome
Noonan Syndrome
Hypertrophic Cardiomyopathy
Mutation
Phosphotransferases
Protein-Serine-Threonine Kinases
Missense Mutation
Cardiomyopathies
Cardiac Myocytes
Hypertrophy

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., ... Gelb, B. D. (2007). Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics, 39(8), 1007-1012. https://doi.org/10.1038/ng2073

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. / Pandit, Bhaswati; Sarkozy, Anna; Pennacchio, Len A.; Carta, Claudio; Oishi, Kimihiko; Martinelli, Simone; Pogna, Edgar A.; Schackwitz, Wendy; Ustaszewska, Anna; Landstrom, Andrew; Bos, J. Martijn; Ommen, Steve R.; Esposito, Giorgia; Lepri, Francesca; Faul, Christian H; Mundel, Peter; López Siguero, Juan P.; Tenconi, Romano; Selicorni, Angelo; Rossi, Cesare; Mazzanti, Laura; Torrente, Isabella; Marino, Bruno; Digilio, Maria C.; Zampino, Giuseppe; Ackerman, Michael J.; Dallapiccola, Bruno; Tartaglia, Marco; Gelb, Bruce D.

In: Nature Genetics, Vol. 39, No. 8, 01.08.2007, p. 1007-1012.

Research output: Contribution to journalArticle

Pandit, B, Sarkozy, A, Pennacchio, LA, Carta, C, Oishi, K, Martinelli, S, Pogna, EA, Schackwitz, W, Ustaszewska, A, Landstrom, A, Bos, JM, Ommen, SR, Esposito, G, Lepri, F, Faul, CH, Mundel, P, López Siguero, JP, Tenconi, R, Selicorni, A, Rossi, C, Mazzanti, L, Torrente, I, Marino, B, Digilio, MC, Zampino, G, Ackerman, MJ, Dallapiccola, B, Tartaglia, M & Gelb, BD 2007, 'Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy', Nature Genetics, vol. 39, no. 8, pp. 1007-1012. https://doi.org/10.1038/ng2073
Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics. 2007 Aug 1;39(8):1007-1012. https://doi.org/10.1038/ng2073
Pandit, Bhaswati ; Sarkozy, Anna ; Pennacchio, Len A. ; Carta, Claudio ; Oishi, Kimihiko ; Martinelli, Simone ; Pogna, Edgar A. ; Schackwitz, Wendy ; Ustaszewska, Anna ; Landstrom, Andrew ; Bos, J. Martijn ; Ommen, Steve R. ; Esposito, Giorgia ; Lepri, Francesca ; Faul, Christian H ; Mundel, Peter ; López Siguero, Juan P. ; Tenconi, Romano ; Selicorni, Angelo ; Rossi, Cesare ; Mazzanti, Laura ; Torrente, Isabella ; Marino, Bruno ; Digilio, Maria C. ; Zampino, Giuseppe ; Ackerman, Michael J. ; Dallapiccola, Bruno ; Tartaglia, Marco ; Gelb, Bruce D. / Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. In: Nature Genetics. 2007 ; Vol. 39, No. 8. pp. 1007-1012.
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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.",
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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 H

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.

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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.

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