C620R mutation of the murine ret proto-oncogene: loss of function effect in homozygotes and possible gain of function effect in heterozygotes

Int J Cancer. 2007 Jul 15;121(2):292-300. doi: 10.1002/ijc.22378.


Germline RET mutations are responsible for different inherited disorders: Hirschsprung disease (congenital aganglionic megacolon), caused by loss of function mutations, familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2, caused by gain of function mutations. Intriguingly, some RET mutations, including C620R, are associated with both types of diseases. To investigate the dual role of such RET mutations, a mouse model with a targeted mutation ret(C620R) was generated. ret(C620R/C620R) offspring die during the first postnatal day, and show kidney agenesis and intestinal aganglionosis. Decreased outgrowth of the Ret-positive cells was observed in ret(C620R/C620R) neuronal cell cultures, which is suggestive of an impaired migration, proliferation or survival of the Ret-expressing cells. Electronmicroscopy revealed the absence of membrane-bound Ret in ret(C620R/C620R) cells as compared to ret(+/+) and ret(+/C620R) cells. On the other hand, aged ret(+/C620R) mice develop precancerous lesions in the adrenal gland or in the thyroid. Our results suggest that the ret(C620R) mutation has a loss of function effect in homozygotes and exhibits a dominant gain of function effect with low penetrance causing hyperplasia in heterozygotes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Adrenal Gland Neoplasms / genetics
  • Adrenal Gland Neoplasms / pathology
  • Amino Acid Substitution
  • Animals
  • Animals, Newborn
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Cells, Cultured
  • Female
  • Heterozygote
  • Hirschsprung Disease / pathology
  • Homozygote
  • Kidney / abnormalities
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Microscopy, Electron
  • Mutation*
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / ultrastructure
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / physiology*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology


  • Proto-Oncogene Proteins c-ret