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

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 retC620R was generated. retC620R/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 retC620R/C620R neuronal cell cultures, which is suggestive of an impaired migration, proliferation or survival of the Retexpressing cells. Electronmicroscopy revealed the absence of membrane- bound Ret in retC620R/C620R cells as compared to ret1/1 and ret1/C620R cells. On the other hand, aged ret1/C620R mice develop precancerous lesions in the adrenal gland or in the thyroid. Our results suggest that the retC620R mutation has a loss of function effect in homozygotes and exhibits a dominant gain of function effect with low penetrance causing hyperplasia in heterozygotes.