The RET C620S mutation causes multiple endocrine neoplasia type 2A (MEN2A) but not Hirschsprung disease (HSCR) in a family cosegregating both phenotypes†

Abstract

The RET proto-oncogene (MIM# 164761), located on chromosome subband 10q11.2, encodes a receptor tyrosine kinase expressed in tissues and tumors derived from the neural crest. The ligands of RET have been identified as growth factors of the glial cell-line–derived neurotrophic factor (GDNF) family, including GDNF, neurturin, artemin, and persephin. All these factors activate RET via different glycosyl phosphatidylinositol– linked GFR a receptors named GFR a 1 to 4. It is thought that the signaling pathways of the protein RET play an important role in differentiation, proliferation, and migration of neural crest cell derivatives, such as thyroid C-cells, adrenal medulla and enteric neurons, as well as other tissues such as parathyroid gland and kidney [Eng, 1999]. Germline gain-of-function mutations of the RET proto-oncogene cause multiple endocrine neoplasia type 2 (MEN2; MIM# 164761) and loss-of-function mutations are associated with a small subset of Hirschsprung disease (HSCR; MIM# 142623). MEN2, the heritable form of medullary thyroid carcinoma (MTC), is believed to account for 25% of all MTC