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C620R mutation of the murine ret proto‐oncogene: Loss of function effect in homozygotes and possible gain of function effect in heterozygotes
Author(s) -
Yin Luo,
Puliti Aldamaria,
Bonora Elena,
Evangelisti Cecilia,
Conti Valerio,
Tong WeiMin,
Medard JeanJacques,
Lavoué MarieFrance,
Forey Nathalie,
Wang Lily C.,
Manié Serge,
Morel Gérard,
Raccurt Mireille,
Wang ZhaoQi,
Romeo Giovanni
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22378
Subject(s) - penetrance , ret proto oncogene , biology , mutation , endocrinology , hyperplasia , multiple endocrine neoplasia type 2 , proto oncogene proteins c ret , medicine , cancer research , medullary carcinoma , thyroid , germline mutation , thyroid carcinoma , phenotype , genetics , gene , receptor , neurotrophic factors , glial cell line derived neurotrophic factor
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. © 2007 Wiley‐Liss, Inc.