Disorders of dysregulated signal traffic through the RAS-MAPK pathway: Phenotypic spectrum and molecular mechanisms

Marco Tartaglia, Bruce D. Gelb

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


RAS GTPases control a major signaling network implicated in several cellular functions, including cell fate determination, proliferation, survival, differentiation, migration, and senescence. Within this network, signal flow through the RAF-MEK-ERK pathway-the first identified mitogen-associated protein kinase (MAPK) cascade-mediates early and late developmental processes controlling morphology determination, organogenesis, synaptic plasticity, and growth. Signaling through the RAS-MAPK cascade is tightly controlled; and its enhanced activation represents a well-known event in oncogenesis. Unexpectedly, in the past few years, inherited dysregulation of this pathway has been recognized as the cause underlying a group of clinically related disorders sharing facial dysmorphism, cardiac defects, reduced postnatal growth, ectodermal anomalies, variable cognitive deficits, and susceptibility to certain malignancies as major features. These disorders are caused by heterozygosity for mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors, or downstream signal transducers. Here, we provide an overview of the phenotypic spectrum associated with germline mutations perturbing RAS-MAPK signaling, the unpredicted molecular mechanisms converging toward the dysregulation of this signaling cascade, and major genotype-phenotype correlations.

Original languageEnglish
Pages (from-to)99-121
Number of pages23
JournalAnnals of the New York Academy of Sciences
Issue number1
StatePublished - Dec 2010


  • Cardiofaciocutaneous syndrome
  • Costello syndrome
  • LEOPARD syndrome
  • Legius syndrome
  • Neurofibromatosis type 1
  • Noonan syndrome
  • Noonan-like syndrome with loose anagen hair
  • RAS signaling


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