Clinical and molecular aspects of RAS related disorders

RAS proteins play key roles in normal cell growth, malignant transformation and learning and memory. Somatic mutations in RAS genes and several of their upstream and downstream molecules result in different human malignancies. In recent years germline mutations in genes coding for components of the RAS signalling cascade have been recognised in a group of phenotypically overlapping disorders, referred to as the neuro-cardio-facial-cutaneous syndromes. These present with variable degrees of psychomotor delay, cardiac abnormalities, facial dysmorphism, short stature, skin defects and increased cancer risk. These findings point to important roles for this evolutionary conserved pathway not only in oncogenesis, but also in cognition, growth and development. Other constitutional disorders caused by mutated RAS pathway genes point to involvement of the RAS-MAPK pathway in immune modulation and vascular development.

[1]  F. Speleman,et al.  Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. , 2006, Human molecular genetics.

[2]  J. Sweatt,et al.  A biochemist's view of long-term potentiation. , 1996, Learning & memory.

[3]  Yoichi Matsubara,et al.  Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype–phenotype relationships and overlap with Costello syndrome , 2007, Journal of Medical Genetics.

[4]  R. Hennekam,et al.  Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome , 2006, Nature Genetics.

[5]  C. Niemeyer,et al.  Germline Mutations in Components of the Ras Signaling Pathway in Noonan Syndrome and Related Disorders , 2006, Cell cycle.

[6]  Matthew Freeman,et al.  Sprouty, an Intracellular Inhibitor of Ras Signaling , 1999, Cell.

[7]  K. Gripp,et al.  Hepatoblastoma and heart transplantation in a patient with cardio‐facio‐cutaneous syndrome , 2007, American journal of medical genetics. Part A.

[8]  D. Horn,et al.  Childhood overgrowth in patients with common NF1 microdeletions , 2005, European Journal of Human Genetics.

[9]  J. Fryns,et al.  PTPN11 mutations in LEOPARD syndrome , 2002, Journal of medical genetics.

[10]  J. Costello.  A New Syndrome: Mental Subnormality and Nasal Papillomata , 1977, Australian paediatric journal.

[11]  Michael J Ackerman,et al.  Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy , 2007, Nature Genetics.

[12]  B. Brownstein,et al.  Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. , 1990, Science.

[13]  F. Beemer,et al.  New syndrome. , 1982, American journal of medical genetics.

[14]  M. Barbacid,et al.  RAS oncogenes: the first 30 years , 2003, Nature Reviews Cancer.

[15]  J. Opitz,et al.  PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome , 2003, European Journal of Human Genetics.

[16]  J. Fryns,et al.  Fine mapping of Noonan/cardio-facio cutaneous syndrome in a large family , 1998, European Journal of Human Genetics.

[17]  D. Horn,et al.  Mutation and phenotypic spectrum in patients with cardio‐facio‐cutaneous and Costello syndrome , 2007, Clinical genetics.

[18]  Claudio Carta,et al.  Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome , 2007, Human mutation.

[19]  J. David Sweatt,et al.  The MAPK cascade is required for mammalian associative learning , 1998, Nature Neuroscience.

[20]  W. Kress,et al.  Genotype-phenotype correlations in Noonan syndrome. , 2004, The Journal of pediatrics.

[21]  R. Foà,et al.  Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. , 2006, American journal of human genetics.

[22]  R. Hennekam,et al.  Molecular and clinical characterization of cardio‐facio‐cutaneous (CFC) syndrome: Overlapping clinical manifestations with Costello syndrome , 2007, American journal of medical genetics. Part A.

[23]  Yukichi Tanaka,et al.  Germline mutations in HRAS proto-oncogene cause Costello syndrome , 2005, Nature Genetics.

[24]  M. Schimek,et al.  Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia. , 2006, Cancer research.

[25]  Wei Zhao,et al.  BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. , 2003, Cancer research.

[26]  J. Sweatt,et al.  Activation of p 42 Mitogen-activated Protein Kinase in Hippocampal Long Term Potentiation * , 1996 .

[27]  Alcino J. Silva,et al.  Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1 , 2002, Nature.

[28]  N. Hacohen,et al.  sprouty Encodes a Novel Antagonist of FGF Signaling that Patterns Apical Branching of the Drosophila Airways , 1998, Cell.

[29]  B. Taylor,et al.  Disodium cromoglycate in childhood asthma. , 1971, The New Zealand medical journal.

[30]  Eric Legius,et al.  Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation , 2008, Human mutation.

[31]  Bruce D Gelb,et al.  Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. , 2006, Human molecular genetics.

[32]  B. Neel,et al.  Stops along the RAS pathway in human genetic disease , 2006, Nature Medicine.

[33]  I. Vetter,et al.  The Guanine Nucleotide-Binding Switch in Three Dimensions , 2001, Science.

[34]  D. Barford,et al.  Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF , 2004, Cell.

[35]  G. Mortier,et al.  Comprehensive NF1 screening on cultured Schwann cells from neurofibromas , 2006, Human mutation.

[36]  J. David Sweatt,et al.  A Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation* , 1997, The Journal of Biological Chemistry.

[37]  M. Teitell,et al.  Mutations in Costello Syndrome : Detection of Constitutional Activating Mutations in Codon 12 and 13 and Loss of Wild-Type Allele in Malignancy , 2005 .

[38]  F. Collins,et al.  Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis , 1993, Nature Genetics.

[39]  Michiko Furutani,et al.  Germline gain-of-function mutations in RAF1 cause Noonan syndrome , 2007, Nature Genetics.

[40]  Li Li,et al.  Germline gain-of-function mutations in SOS1 cause Noonan syndrome , 2007, Nature Genetics.

[41]  Wendy Schackwitz,et al.  Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome , 2006, Nature Genetics.

[42]  R. Kucherlapati,et al.  K-ras is an essential gene in the mouse with partial functional overlap with N-ras. , 1997, Genes & development.

[43]  A. Ortega,et al.  Activation of p42 Mitogen-Activated Protein Kinase by Glutamate in Cultured Radial Glia , 1997, Neurochemical Research.

[44]  S. Pilotti,et al.  Elevated risk for MPNST in NF1 microdeletion patients. , 2003, American journal of human genetics.

[45]  Stefan Mundlos,et al.  Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations , 2006, Journal of Medical Genetics.

[46]  J. David Sweatt,et al.  Activation of p42 Mitogen-activated Protein Kinase in Hippocampal Long Term Potentiation* , 1996, The Journal of Biological Chemistry.

[47]  E. Zackai,et al.  Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol. , 2002, American journal of medical genetics.

[48]  J. Hoffman,et al.  Somatic mosaicism for an HRAS mutation causes Costello syndrome , 2006, American journal of medical genetics. Part A.

[49]  J. Opitz,et al.  The cardiofaciocutaneous syndrome , 2006, Journal of Medical Genetics.

[50]  E. Mariman,et al.  Further Delineation of the Critical Region for Noonan Syndrome on the Long Arm of Chromosome 12 , 1997, European journal of human genetics : EJHG.

[51]  M. Loh,et al.  The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. , 2005, Blood.

[52]  A. Battaglia,et al.  NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. , 2005, American journal of human genetics.

[53]  E. Mariman,et al.  Mapping a gene for Noonan syndrome to the long arm of chromosome 12 , 1994, Nature Genetics.

[54]  Peter J. Munson,et al.  NRAS mutation causes a human autoimmune lymphoproliferative syndrome , 2007, Proceedings of the National Academy of Sciences.

[55]  M. Malumbres,et al.  Mice deficient for N-ras: impaired antiviral immune response and T-cell function. , 2003, Cancer research.

[56]  K Kozlowski,et al.  A new syndrome? Unusual facies, hooked clavicles, 13 pairs of ribs, widened metaphyses, square shaped vertebral bodies and communicating hydrocephalus. , 1992, Pediatric radiology.

[57]  E. Legius,et al.  Intelligence in individuals with a neurofibromatosis type 1 microdeletion , 2004, American journal of medical genetics. Part A.

[58]  Frank McCormick,et al.  Nonsense mutations in the C–terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours , 1993, Nature Genetics.

[59]  Gideon Bollag,et al.  GTPase activating proteins: critical regulators of intracellular signaling. , 2002, Biochimica et biophysica acta.

[60]  P. O'Connell,et al.  A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations , 1990, Cell.

[61]  Miikka Vikkula,et al.  Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. , 2003, American journal of human genetics.

[62]  D. Horn,et al.  SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome , 2007, Journal of Medical Genetics.

[63]  P. O'Connell,et al.  Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. , 1994, The New England journal of medicine.

[64]  J. Miyazaki,et al.  Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. , 2004, The Journal of clinical investigation.

[65]  Michael A. Patton,et al.  Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome , 2001, Nature Genetics.

[66]  M. Garnett,et al.  Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. , 2005, Cancer research.

[67]  E. Zackai,et al.  Further delineation of cardiac abnormalities in Costello syndrome. , 2002, American journal of medical genetics.

[68]  M. Digilio,et al.  Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. , 2002, American journal of human genetics.

[69]  R. Baron,et al.  Spred is a Sprouty-related suppressor of Ras signalling , 2001, Nature.

[70]  R. Hennekam.  Costello syndrome: An overview , 2003, American journal of medical genetics. Part C, Seminars in medical genetics.

[71]  Kam Y. J. Zhang,et al.  Germline KRAS mutations cause Noonan syndrome , 2006, Nature Genetics.

[72]  J. Lambert,et al.  Somatic mutation analysis in NF1 café au lait spots reveals two NF1 hits in the melanocytes. , 2008, The Journal of investigative dermatology.

[73]  John Mendelsohn,et al.  The EGF receptor family as targets for cancer therapy , 2000, Oncogene.

[74]  W. Reardon,et al.  Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases , 2005, Journal of Medical Genetics.

[75]  J. Krieger,et al.  Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene , 2007, Journal of Human Genetics.

[76]  W. Kolch.  Coordinating ERK/MAPK signalling through scaffolds and inhibitors , 2005, Nature Reviews Molecular Cell Biology.

[77]  Mary L Marazita,et al.  A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. , 2002, American journal of human genetics.

[78]  K. Shannon,et al.  Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras , 1994 .

[79]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[80]  Y. Makita,et al.  Leukemia in Cardio-facio-cutaneous (CFC) Syndrome: A Patient With a Germline Mutation in BRAF Proto-oncogene , 2007, Journal of pediatric hematology/oncology.

[81]  B. Shilo,et al.  Sprouty is a general inhibitor of receptor tyrosine kinase signaling. , 1999, Development.

[82]  C. Der,et al.  Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[83]  B. Gelb,et al.  Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. , 2006, American journal of human genetics.

[84]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[85]  G. Thomas,et al.  Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1–like phenotype , 2007, Nature Genetics.

[86]  T. Pawson,et al.  Vascular system defects and neuronal apoptosis in mice lacking Ras GTPase-activating protein , 1995, Nature.

[87]  Suzanne Schubbert,et al.  Deregulated Ras signaling in developmental disorders: new tricks for an old dog. , 2007, Current opinion in genetics & development.

[88]  J. Licht,et al.  Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia , 2003, Nature Genetics.

[89]  J. Mulliken,et al.  Locus for susceptibility for familial capillary malformation (‘port-wine stain’) maps to 5q , 2002, European Journal of Human Genetics.

[90]  K. Jones,et al.  Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio‐facio‐cutaneous syndrome from Costello syndrome , 2007, American journal of medical genetics. Part A.

[91]  K. Gripp.  Tumor predisposition in Costello syndrome , 2005, American journal of medical genetics. Part C, Seminars in medical genetics.

[92]  M. Loh,et al.  SOS1 mutations are rare in human malignancies: Implications for Noonan syndrome patients , 2008, Genes, chromosomes & cancer.

[93]  E. Zackai,et al.  HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation , 2006, American journal of medical genetics. Part A.

[94]  E. Legius,et al.  Multifocal glomus tumours of the fingers in two patients with neurofibromatosis type 1 , 2002, Journal of medical genetics.

[95]  P. O'Connell,et al.  Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus , 1990, Cell.

[96]  J. Sweatt,et al.  A necessity for MAP kinase activation in mammalian spatial learning. , 1999, Learning & memory.

[97]  Pablo Rodriguez-Viciana,et al.  Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome , 2006, Science.

[98]  Mathew J Garnett,et al.  Guilty as charged: B-RAF is a human oncogene. , 2004, Cancer cell.

[99]  Frank McCormick,et al.  Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options. , 2007, Human molecular genetics.