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Deregulated Ras signaling in developmental disorders: new tricks for an old dog

Suzanne Schubbert1, Gideon Bollag, Kevin Shannon

  • 1Department of Pediatrics, University of California, 513 Parnassus Avenue, Room HSE-302, San Francisco, CA 94143, USA.

Current Opinion in Genetics & Development
|January 9, 2007
PubMed

Insights

Ras signaling is crucial for human development. Germline mutations in Ras pathway genes cause developmental disorders with shared traits like abnormal facial features and heart defects.

Area of Science:

  • Molecular Biology
  • Genetics
  • Developmental Biology

Background:

  • Ras proteins are key regulators of cell growth, survival, and differentiation.
  • Constitutive activation of Ras proteins by somatic mutations is common in various cancers.
  • Hyperactive Ras signaling has been previously linked to developmental disorders like neurofibromatosis type 1 and Noonan syndrome.

Purpose of the Study:

  • To investigate the role of germline mutations in Ras pathway genes in developmental disorders.
  • To identify specific genes and mutations associated with Noonan, cardio-facio-cutaneous, and Costello syndromes.
  • To underscore the critical involvement of Ras signaling in human development.

Main Methods:

  • Analysis of germline mutations in H-RAS, K-RAS, and other genes within the Ras-Raf-MEK-ERK pathway.
  • Phenotypic characterization of individuals with identified mutations.
  • Correlation of specific mutations with clinical manifestations.

Main Results:

  • Germline mutations in H-RAS, K-RAS, and other Ras-Raf-MEK-ERK cascade genes underlie Noonan, cardio-facio-cutaneous, and Costello syndromes.
  • These syndromes share common phenotypic traits, including dysmorphic facial features, cardiac defects, and impaired growth and development.
  • Many disease-associated mutations identified encode novel Ras, Raf, and MEK proteins, indicating altered protein function.

Conclusions:

  • Ras signaling plays a fundamental role in human development.
  • Germline mutations in the Ras pathway are a significant cause of syndromic developmental disorders.
  • Understanding these mutations provides insights into developmental processes and potential therapeutic targets.

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