Hostname: page-component-669899f699-rg895 Total loading time: 0 Render date: 2025-04-28T05:48:49.923Z Has data issue: false hasContentIssue false
  • English
  • Français

Noonan, Costello and cardio–facio–cutaneous syndromes: dysregulation of the Ras–MAPK pathway

Published online by Cambridge University Press:  09 December 2008

William E. Tidyman  and
Katherine A. Rauen
William E. Tidyman
Affiliation:
Department of Anatomy, University of CaliforniaSan Francisco, CA, USA.
Katherine A. Rauen*
Affiliation:
Department of Pediatrics, Division of Medical Genetics, University of CaliforniaSan Francisco, CA, USA. UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
*
*Corresponding author: Katherine A. Rauen, UCSF Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, Room S429, Box 0128, San Francisco, CA 94115, USA. Tel: +1 415 514 3513; Fax: +1 415 502 3179; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

A class of developmental disorders caused by dysregulation of the Ras-induced mitogen-activated protein kinase (MAPK) cascade (the Ras–MAPK pathway) has emerged. Three of these disorders – Noonan, Costello and cardio–facio–cutaneous syndromes – have overlapping phenotypic features characterised by distinctive facial dysmorphia, cardiac defects, musculoskeletal and cutaneous abnormalities, and neurocognitive delay. The germline mutations associated with these disorders are in genes that encode proteins of the Ras–MAPK pathway. In vitro studies have determined that the overwhelming majority of these mutations result in increased signal transduction down the pathway, but usually to a lesser degree than somatic mutations in the same genes that are associated with cancer. The Ras–MAPK pathway is essential in the regulation of the cell cycle, differentiation, growth and senescence, so it is not surprising that germline mutations that affect its function have profound effects on development. Here we review the clinical consequences of the known molecular lesions associated with Noonan syndrome, Costello syndrome and cardio–facio–cutaneous syndrome, and explore possible therapeutic modalities for treatment.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e37
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

References

1Hancock, J.F. (2003) Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol 4, 373-384CrossRefGoogle ScholarPubMed
2Bos, J.L. (1989) ras oncogenes in human cancer: a review. Cancer Res 49, 4682-4689Google ScholarPubMed
3Midgley, R.S. and Kerr, D.J. (2002) Ras as a target in cancer therapy. Crit Rev Oncol Hematol 44, 109-120CrossRefGoogle ScholarPubMed
4Yoon, S. and Seger, R. (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24, 21-44Google Scholar
5Haccard, O. et al. (1995) Induction of Xenopus oocyte meiotic maturation by MAP kinase. Dev Biol 168, 677-682CrossRefGoogle ScholarPubMed
6Haccard, O. et al. (1993) Induction of metaphase arrest in cleaving Xenopus embryos by MAP kinase. Science 262, 1262-1265Google Scholar
7Haccard, O. et al. (1993) Mitogen-activated protein kinase (MAP kinase) activation in Xenopus oocytes: roles of MPF and protein synthesis. Mol Reprod Dev 36, 96-105Google Scholar
8Curran, K.L. and Grainger, R.M. (2000) Expression of activated MAP kinase in Xenopus laevis embryos: evaluating the roles of FGF and other signaling pathways in early induction and patterning. Dev Biol 228, 41-56CrossRefGoogle ScholarPubMed
9Gotoh, Y. et al. (1995) Involvement of the MAP kinase cascade in Xenopus mesoderm induction. EMBO J 14, 2491-2498Google Scholar
10Gotoh, Y. and Nishida, E. (1995) Activation mechanism and function of the MAP kinase cascade. Mol Reprod Dev 42, 486-492CrossRefGoogle ScholarPubMed
11Gabay, L., Seger, R. and Shilo, B.Z. (1997) MAP kinase in situ activation atlas during Drosophila embryogenesis. Development 124, 3535-3541Google Scholar
12Furthauer, M. et al. (2004) Fgf signalling controls the dorsoventral patterning of the zebrafish embryo. Development 131, 2853-2864CrossRefGoogle ScholarPubMed
13Corson, L.B. et al. (2003) Spatial and temporal patterns of ERK signaling during mouse embryogenesis. Development 130, 4527-4537CrossRefGoogle ScholarPubMed
14Leichtman, L.G. (1996) Are cardio-facio-cutaneous syndrome and Noonan syndrome distinct? A case of CFC offspring of a mother with Noonan syndrome. Clin Dysmorphol 5, 61-64CrossRefGoogle ScholarPubMed
15Fryer, A.E., Holt, P.J. and Hughes, H.E. (1991) The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same? Am J Med Genet 38, 548-551CrossRefGoogle ScholarPubMed
16Neri, G. and Zollino, M. (1996) More on the Noonan-CFC controversy [editorial; comment]. Am J Med Genet 65, 100Google Scholar
17Neri, G. and Opitz, J.M. (2000) Heterogeneity of cardio-facio-cutaneous syndrome. Am J Med Genet 95, 1443.0.CO;2-E>CrossRefGoogle ScholarPubMed
18Tartaglia, M. et al. (2003) Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes. Clin Genet 63, 423-426CrossRefGoogle ScholarPubMed
19Noonan, J.A. (1968) Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am J Dis Child 116, 373-380Google Scholar
20Shaw, A.C. et al. (2007) The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child 92, 128-132Google Scholar
21Lin, A.E. (1988) Noonan syndrome. J Med Genet 25, 64-65Google Scholar
22Reynolds, D.J. et al. (2004) Ocular manifestations of Noonan syndrome in the pediatric patient. J AAPOS 8, 282-283Google Scholar
23Massarano, A.A. et al. (1996) Noonan syndrome: coagulation and clinical aspects. Acta Paediatr 85, 1181-1185Google Scholar
24Lee, D.A. et al. (2005) Psychological profile of children with Noonan syndrome. Dev Med Child Neurol 47, 35-38Google Scholar
25Holder-Espinasse, M. and Winter, R.M. (2003) Type 1 Arnold-Chiari malformation and Noonan syndrome. A new diagnostic feature? Clin Dysmorphol 12, 275CrossRefGoogle ScholarPubMed
26Choong, K. et al. (1999) Juvenile myelomonocytic leukemia and Noonan syndrome. J Pediatr Hematol Oncol 21, 523-527Google Scholar
27Attard-Montalto, S.P., Kingston, J.E. and Eden, T. (1994) “Noonan's syndrome and acute lymphoblastic leukaemia”. Med Pediatr Oncol 23, 391-392Google Scholar
28Bader-Meunier, B. et al. (1997) Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J Pediatr 130, 885-889Google Scholar
29Moschovi, M. et al. (2007) Rhabdomyosarcoma in a patient with Noonan syndrome phenotype and review of the literature. J Pediatr Hematol Oncol 29, 341-344CrossRefGoogle Scholar
30Roti, G. et al. (2006) Acute lymphoblastic leukaemia in Noonan syndrome. Br J Haematol 133, 448-450CrossRefGoogle ScholarPubMed
31Piombo, M. et al. (1993) Acute lymphoblastic leukemia in Noonan syndrome: report of two cases. Med Pediatr Oncol 21, 454-455CrossRefGoogle ScholarPubMed
32Tartaglia, M. et al. (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29, 465-468CrossRefGoogle ScholarPubMed
33Roberts, A.E. et al. (2007) Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 39, 70-74Google Scholar
34Tartaglia, M. et al. (2007) Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 39, 75-79Google Scholar
35Pandit, B. et al. (2007) Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 39, 1007-1012Google Scholar
36Razzaque, M.A. et al. (2007) Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 39, 1013-1017Google Scholar
37Schubbert, S. et al. (2006) Germline KRAS mutations cause Noonan syndrome. Nat Genet 38, 331-336CrossRefGoogle ScholarPubMed
38Zenker, M. et al. (2007) Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet 44, 131-135CrossRefGoogle ScholarPubMed
39Tartaglia, M. et al. (2002) PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 70, 1555-1563Google Scholar
40Hof, P. et al. (1998) Crystal structure of the tyrosine phosphatase SHP-2. Cell 92, 441-450CrossRefGoogle ScholarPubMed
41Keilhack, H. et al. (2005) Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem 280, 30984-30993CrossRefGoogle ScholarPubMed
42Tartaglia, M. et al. (2006) Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet 78, 279-290Google Scholar
43Fragale, A. et al. (2004) Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat 23, 267-277CrossRefGoogle ScholarPubMed
44Niihori, T. et al. (2005) Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J Hum Genet 50, 192-202Google Scholar
45Araki, T. et al. (2004) Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med 10, 849-857Google Scholar
46O'Reilly, A.M. et al. (2000) Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Mol Cell Biol 20, 299-311Google Scholar
47Martinelli, S. et al. (2008) Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Hum Mol Genet 17, 2018-2029Google Scholar
48Kratz, C.P. et al. (2005) The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106, 2183-2185Google Scholar
49Tartaglia, M. et al. (2004) Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 104, 307-313CrossRefGoogle ScholarPubMed
50Bentires-Alj, M. et al. (2004) Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res 64, 8816-8820Google Scholar
51Chen, Y. et al. (2006) Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies. Genes Chromosomes Cancer 45, 583-591Google Scholar
52Loh, M.L. et al. (2004) Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103, 2325-2331CrossRefGoogle ScholarPubMed
53Miyamoto, D. et al. (2008) Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors. Oncogene 27, 3508-3515Google Scholar
54Schubbert, S. et al. (2005) Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood 106, 311-317CrossRefGoogle ScholarPubMed
55Yoshida, R. et al. (2008) Hepatoblastoma in a Noonan syndrome patient with a PTPN11 mutation. Pediatr Blood Cancer 50, 1274-1276Google Scholar
56Tartaglia, M. et al. (2004) Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Am J Hum Genet 75, 492-497Google Scholar
57Friday, B.B. and Adjei, A.A. (2005) K-ras as a target for cancer therapy. Biochim Biophys Acta 1756, 127-144Google Scholar
58Niihori, T. et al. (2006) Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 38, 294-296Google Scholar
59Schubbert, S. et al. (2007) Biochemical and functional characterization of germ line KRAS mutations. Mol Cell Biol 27, 7765-7770Google Scholar
60Carta, C. et al. (2006) Germline missense mutations affecting KRAS isoform B are associated with a severe noonan syndrome phenotype. Am J Hum Genet 79, 129-135Google Scholar
61Zenker, M. et al. (2007) SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet 44, 651-656CrossRefGoogle ScholarPubMed
62Swanson, K.D. et al. (2008) SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients. Genes Chromosomes Cancer 47, 253-259Google Scholar
63Emuss, V. et al. (2005) Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res 65, 9719-9726Google Scholar
64Costello, J.M. (1971) A new syndrome. N Z Med J 74, 397Google Scholar
65Costello, J.M. (1977) A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J 13, 114-118Google ScholarPubMed
66Hennekam, R.C. (2003) Costello syndrome: an overview. Am J Med Genet C Semin Med Genet 117, 42-48Google Scholar
67Rauen, K.A. (2007) HRAS and the Costello syndrome. Clin Genet 71, 101-108Google Scholar
68Yassir, W.K., Grottkau, B.E. and Goldberg, M.J. (2003) Costello syndrome: orthopaedic manifestations and functional health. J Pediatr Orthop 23, 94-98CrossRefGoogle ScholarPubMed
69Lin, A.E. et al. (2002) Further delineation of cardiac abnormalities in Costello syndrome. Am J Med Genet 111, 115-129Google Scholar
70Axelrad, M.E. et al. (2007) Longitudinal assessment of cognitive characteristics in Costello syndrome. Am J Med Genet A 143A, 3185-3193CrossRefGoogle ScholarPubMed
71Delrue, M.A. et al. (2003) Costello syndrome and neurological abnormalities. Am J Med Genet A 123, 301-305Google Scholar
72Gregersen, N. and Viljoen, D. (2004) Costello syndrome with growth hormone deficiency and hypoglycemia: a new report and review of the endocrine associations. Am J Med Genet A 129, 171-175CrossRefGoogle Scholar
73Stein, R.I. et al. (2004) Growth hormone deficiency in Costello syndrome. Am J Med Genet A 129, 166-170Google Scholar
74Estep, A.L. et al. (2006) HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A 140, 8-16CrossRefGoogle ScholarPubMed
75Kawame, H. et al. (2003) Further delineation of the behavioral and neurologic features in Costello syndrome. Am J Med Genet A 118, 8-14CrossRefGoogle Scholar
76Galera, C. et al. (2006) Behavioral and temperamental features of children with Costello syndrome. Am J Med Genet A 140, 968-974Google Scholar
77Gripp, K.W. (2005) Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 137, 72-77Google Scholar
78Gordon, T. et al. (2001) Cytogenetic abnormalities in 42 rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics Group Study. Med Pediatr Oncol 36, 259-267Google Scholar
79Tobar, A. et al. (2000) Clinical relevance of molecular diagnosis in childhood rhabdomyosarcoma. Diagn Mol Pathol 9, 9-13Google Scholar
80Gripp, K.W. et al. (2002) Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol. Am J Med Genet 108, 80-87Google Scholar
81Aoki, Y. et al. (2005) Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37, 1038-1040Google Scholar
82Gripp, K.W. et al. (2006) HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation. Am J Med Genet A 140, 1-7Google Scholar
83Kerr, B. et al. (2006) Genotype-phenotype correlation in Costello syndrome; HRAS mutation analysis in 43 cases. J Med Genet 43, 401-405Google Scholar
84Lo, I.F. et al. (2008) Severe neonatal manifestations of Costello syndrome. J Med Genet 45, 167-171Google Scholar
85Schulz, A.L. et al. (2008) Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. Clin Genet 73, 62-70Google Scholar
86van der Burgt, I. et al. (2007) Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. J Med Genet 44, 459-462Google Scholar
87van Steensel, M.A. et al. (2006) Recurring HRAS mutation G12S in Dutch patients with Costello syndrome. Exp Dermatol 15, 731-734Google Scholar
88Zampino, G. et al. (2007) Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat 28, 265-272CrossRefGoogle ScholarPubMed
89Denayer, E. et al. (2008) Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation. Hum Mutat 29, 232-239Google Scholar
90Gripp, K.W. et al. (2008) Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? Am J Med Genet A 146A, 683-690CrossRefGoogle ScholarPubMed
91Rauen, K.A. (2006) Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. Am J Med Genet A 140, 1681-1683CrossRefGoogle ScholarPubMed
92Kerr, B. et al. (2008) The diagnosis of Costello syndrome: nomenclature in Ras/MAPK pathway disorders. Am J Med Genet 146A, 1218-1220CrossRefGoogle ScholarPubMed
93Sol-Church, K. et al. (2006) Paternal bias in parental origin of HRAS mutations in Costello syndrome. Hum Mutat 27, 736-741CrossRefGoogle ScholarPubMed
94Gripp, K.W. et al. (2006) Somatic mosaicism for an HRAS mutation causes Costello syndrome. Am J Med Genet A 140, 2163-2169CrossRefGoogle ScholarPubMed
95Gibbs, J.B. et al. (1984) Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc Natl Acad Sci U S A 81, 5704-5708CrossRefGoogle ScholarPubMed
96McGrath, J.P. et al. (1984) Comparative biochemical properties of normal and activated human ras p21 protein. Nature 310, 644-649Google Scholar
97Sweet, R.W. et al. (1984) The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature 311, 273-275Google Scholar
98Seeburg, P.H. et al. (1984) Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 312, 71-75CrossRefGoogle ScholarPubMed
99Fasano, O. et al. (1984) Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc Natl Acad Sci U S A 81, 4008-4012CrossRefGoogle ScholarPubMed
100Newbold, R.F. and Overell, R.W. (1983) Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature 304, 648-651CrossRefGoogle ScholarPubMed
101Land, H., Parada, L.F. and Weinberg, R.A. (1983) Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304, 596-602Google Scholar
102Hahn, W.C. et al. (1999) Creation of human tumour cells with defined genetic elements. Nature 400, 464-468Google Scholar
103Levesque, P. et al. (1993) Screening of human bladder tumors and urine sediments for the presence of H-ras mutations. Int J Cancer 55, 785-790CrossRefGoogle ScholarPubMed
104Takahashi, Y. et al. (2004) Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma. Mod Pathol 17, 660-669CrossRefGoogle ScholarPubMed
105Yoo, J. and Robinson, R.A. (1999) H-ras and K-ras mutations in soft tissue sarcoma: comparative studies of sarcomas from Korean and American patients. Cancer 86, 58-63Google Scholar
106Kerr, B. et al. (2003) Is the locus for Costello syndrome on 11p? J Med Genet 40, 469-471Google Scholar
107Blumberg, B. et al. (1979) A new mental retardation syndrome with characterisitc facies, ichthyosis and abnormal hair. March of Dimes Birth Defects ConferenceChicago, Il, USAGoogle Scholar
108Reynolds, J.F. et al. (1986) New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement–the CFC syndrome. Am J Med Genet 25, 413-427Google Scholar
109Borradori, L. and Blanchet-Bardon, C. (1993) Skin manifestations of cardio-facio-cutaneous syndrome. J Am Acad Dermatol 28, 815-819Google Scholar
110Weiss, G. et al. (2004) Cutaneous manifestations in the cardiofaciocutaneous syndrome, a variant of the classical Noonan syndrome. Report of a case and review of the literature. J Eur Acad Dermatol Venereol 18, 324-327CrossRefGoogle ScholarPubMed
111Wieczorek, D., Majewski, F. and Gillessen-Kaesbach, G. (1997) Cardio-facio-cutaneous (CFC) syndrome–a distinct entity? Report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome. Clin Genet 52, 37-46CrossRefGoogle ScholarPubMed
112Young, T.L., Ziylan, S. and Schaffer, D.B. (1993) The ophthalmologic manifestations of the cardio-facio-cutaneous syndrome. J Pediatric Ophthalmol Strabismus 30, 48-52Google Scholar
113Grebe, T.A. and Clericuzio, C. (2000) Neurologic and gastrointestinal dysfunction in cardio-facio-cutaneous syndrome: identification of a severe phenotype. Am J Med Genet 95, 135-1433.0.CO;2-J>CrossRefGoogle ScholarPubMed
114Sabatino, G. et al. (1997) The cardio-facio-cutaneous syndrome: a long-term follow-up of two patients, with special reference to the neurological features. Childs Nerv Syst 13, 238-241Google Scholar
115Herman, T.E. and McAlister, W.H. (2005) Gastrointestinal and renal abnormalities in cardio-facio-cutaneous syndrome. Pediatr Radiol 35, 202-205CrossRefGoogle ScholarPubMed
116Chan, P.C., Chiu, H.C. and Hwu, W.L. (2002) Spontaneous chylothorax in a case of cardio-facio-cutaneous syndrome. Clin Dysmorphol 11, 297-298Google Scholar
117Yoon, G. et al. (2007) Neurological complications of cardio-facio-cutaneous syndrome. Dev Med Child Neurol 49, 894-899Google Scholar
118Van Den Berg, H., Hennekam, R.C.M. (1999) Acute lymphoblastic leukaemia in a patient with cardiofaciocutaneous syndrome. J Med Genet 36, 799-800Google Scholar
119Makita, Y. et al. (2007) Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene. J Pediatr Hematol Oncol 29, 287-290Google Scholar
120Al-Rahawan, M.M. et al. (2007) Hepatoblastoma and heart transplantation in a patient with cardio-facio-cutaneous syndrome. Am J Med Genet A 143, 1481-1488Google Scholar
121Rodriguez-Viciana, P. et al. (2006) Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311, 1287-1290Google Scholar
122Wellbrock, C., Karasarides, M. and Marais, R. (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5, 875-885Google Scholar
123Narumi, Y. et al. (2007) Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: Overlapping clinical manifestations with Costello syndrome. Am J Med Genet A 143, 799-807Google Scholar
124Nava, C. et al. (2007) Cardio-facio-cutaneous and Noonan syndromes due to mutations in RAS/MAPK signaling pathway: genotype/phenotype relationships and overlap with Costello syndrome. J Med Genet 44, 763-771Google Scholar
125Gripp, K.W. et al. (2007) Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am J Med Genet A 143A, 1472-1480Google Scholar
126Wan, P.T. et al. (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855-867CrossRefGoogle ScholarPubMed
127Garnett, M.J. et al. (2005) Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell 20, 963-969Google Scholar
128Davies, H. et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417, 949-954CrossRefGoogle ScholarPubMed
129Yuen, S.T. et al. (2002) Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62, 6451-6455Google Scholar
130Rajagopalan, H. et al. (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418, 934Google Scholar
131Pollock, P.M. et al. (2003) High frequency of BRAF mutations in nevi. Nat Genet 33, 19-20CrossRefGoogle ScholarPubMed
132Pearson, G. et al. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22, 153-183Google Scholar
133Wu, J. et al. (1993) Identification and characterization of a new mammalian mitogen-activated protein kinase kinase, MKK2. Mol Cell Biol 13, 4539-4548Google Scholar
134Brott, B.K. et al. (1993) MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. Cell Growth Differ 4, 921-929Google Scholar
135Alessandrini, A., Brott, B.K. and Erikson, R.L. (1997) Differential expression of MEK1 and MEK2 during mouse development. Cell Growth Differ 8, 505-511Google ScholarPubMed
136Cowley, S. et al. (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77, 841-852CrossRefGoogle ScholarPubMed
137Mansour, S.J. et al. (1994) Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265, 966-970CrossRefGoogle ScholarPubMed
138Sivaraman, V.S. et al. (1997) Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest 99, 1478-1483Google Scholar
139Hoshino, R. et al. (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18, 813-822Google Scholar
140Bignell, G. et al. (2006) Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults. Genes Chromosomes Cancer 45, 42-46Google Scholar
141Davies, H. et al. (2005) Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res 65, 7591-7595Google Scholar
142Hunter, C. et al. (2006) A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res 66, 3987-3991Google Scholar
143Stephens, P. et al. (2005) A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat Genet 37, 590-592Google Scholar
144Estep, A.L. et al. (2007) Mutation Analysis of BRAF, MEK1 and MEK2 in 15 Ovarian Cancer Cell Lines: Implications for Therapy. PLoS ONE 2, e1279CrossRefGoogle ScholarPubMed
145Nakamura, T. et al. (2007) Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome. J Clin Invest 117, 2123-2132Google Scholar
146Schuhmacher, A.J. et al. (2008) A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition. J Clin Invest 118, 2169-2179Google Scholar
147Mercer, K. et al. (2005) Expression of endogenous oncogenic V600EB-raf induces proliferation and developmental defects in mice and transformation of primary fibroblasts. Cancer Res 65, 11493-11500Google Scholar
148Wojnowski, L. et al. (2000) Overlapping and specific functions of Braf and Craf-1 proto-oncogenes during mouse embryogenesis. Mech Dev 91, 97-104Google Scholar
149Galabova-Kovacs, G. et al. (2006) Essential role of B-Raf in ERK activation during extraembryonic development. Proc Natl Acad Sci U S A 103, 1325-1330Google Scholar
150Giroux, S. et al. (1999) Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol 9, 369-372Google Scholar
151Belanger, L.F. et al. (2003) Mek2 is dispensable for mouse growth and development. Mol Cell Biol 23, 4778-4787Google Scholar
152Scholl, F.A. et al. (2007) Mek1/2 MAPK kinases are essential for Mammalian development, homeostasis, and Raf-induced hyperplasia. Dev Cell 12, 615-629Google Scholar
153Sebolt-Leopold, J.S. and Herrera, R. (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4, 937-947Google Scholar
154Sebolt-Leopold, J.S. (2008) Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway. Clin Cancer Res 14, 3651-3656Google Scholar
155Tsai, J. et al. (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 105, 3041-3046CrossRefGoogle ScholarPubMed
156Senawong, T. et al. (2008) Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options. Hum Mol Genet 17, 419-430CrossRefGoogle ScholarPubMed
157Solit, D.B. et al. (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358-362CrossRefGoogle ScholarPubMed
158Digilio, M.C. et al. (2002) Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71, 389-394CrossRefGoogle ScholarPubMed
159Hart, T.C. et al. (2002) A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. Am J Hum Genet 70, 943-954Google Scholar
160Eerola, I. et al. (2003) Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 73, 1240-1249CrossRefGoogle ScholarPubMed
161Cawthon, R.M. et al. (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62, 193-201Google Scholar
162Viskochil, D. et al. (1990) Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187-192CrossRefGoogle Scholar
163Wallace, M.R. et al. (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181-186Google Scholar
164Brems, H. et al. (2007) Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 39, 1120-1126Google Scholar

Further reading, resources and contacts

Clinical genetics reviews on Noonan, Costello and cardio-facio-cutaneous syndrome can be found at GeneTests:

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=noonanGoogle Scholar
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=costelloGoogle Scholar
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cfcGoogle Scholar
http://stke.sciencemag.org/Google Scholar
http://www.signaling-gateway.org/update/Google Scholar
http://www.noonansyndrome.org (Noonan Syndrome Support Group)Google Scholar
http://www.costellokids.com (International Costello Syndrome Support Group)Google Scholar
http://www.cfcsyndrome.org (CFC International)Google Scholar