Loss of function effect of RET mutations causing Hirschsprung disease

Nat Genet. 1995 May;10(1):35-40. doi: 10.1038/ng0595-35.


We have introduced three Hirschsprung (HSCR) mutations localized in the tyrosine kinase domain of RET into the RET/PTC2 chimaeric oncogene which is capable of transforming NIH3T3 mouse fibroblasts and of differentiating pC12 rat pheochromocytoma cells. The three HSCR mutations abolished the biological activity of RET/PTC2 in both cell types and significantly decreased its tyrosine phosphorylation. By contrast, a rare polymorphism in exon 18 does not alter the transforming capability of RET/PTC2 or its tyrosine phosphorylation. These data suggest a loss of function effect of HSCR mutations which might act through a dominant negative mechanism. Our model system is therefore capable of discriminating between causative HSCR mutations and rare polymorphisms in the tyrosine kinase domain of RET.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Base Sequence
  • Cell Differentiation
  • Cell Transformation, Neoplastic
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Drosophila Proteins*
  • Exons
  • Genetic Complementation Test
  • HeLa Cells
  • Hirschsprung Disease / genetics*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation*
  • PC12 Cells
  • Phosphorylation
  • Precipitin Tests
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-ret
  • Rats
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / physiology
  • Transfection
  • Tyrosine / metabolism


  • Drosophila Proteins
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Tyrosine
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, mouse
  • Ret protein, rat
  • Cyclic AMP-Dependent Protein Kinases