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Co‐segregation of MEN2 and Hirschsprung's disease: The same mutation of RET with both gain and loss‐of‐function?
Author(s) -
Takahashi Masahide,
Iwashita Toshihide,
Santoro Massimo,
Lyonnet Stanislas,
Lenoir Gilbert M.,
Billaud Marc
Publication year - 1999
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/(sici)1098-1004(1999)13:4<331::aid-humu11>3.0.co;2-#
Subject(s) - multiple endocrine neoplasia type 2 , glial cell line derived neurotrophic factor , biology , neurturin , hirschsprung's disease , proto oncogene proteins c ret , interstitial cell of cajal , pheochromocytoma , receptor tyrosine kinase , cancer research , medicine , neurotrophic factors , germline mutation , endocrinology , receptor , mutation , genetics , gene , disease , smooth muscle
Multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung's disease (HSCR) are two dominantly inherited neurocristopathies ascribed to mutations in the RET gene [Chakravarti, 1996; Pasini et al., 1996; Eng and Mulligan, 1997]. MEN2 is a cancer syndrome comprising three related clinical subtypes: (1) MEN type 2A (MEN2A; MIM# 171400) characterized by the association of medullary thyroid carcinoma (MTC), pheochromocytoma (Pheo), and hyperparathyroidism; (2) MEN type 2B (MEN2B; MIM# 162300), which includes MTC, Pheo, mucosal neuromas, ganglioneuromatosis of the digestive tract, and skeletal abnormalities; and (3) familial MTC (FMTC; MIM# 155240), defined by the sole occurrence of MTC. HSCR (MIM# 142623) is a congenital malformation caused by the absence of enteric plexuses in the hindgut, leading to bowel obstruction in neonates. The RET gene (MIM# 164761) codes for a transmembrane tyrosine kinase, a component of a multimeric complex that also comprises one of four members of a novel family of glycosylphosphatidylinositol (GPI)‐anchored receptor, GFRα(1–4) (e.g., GFRA1, MIM# 601496; references are detailed in Baloh et al. [1998]. Four structurally related soluble factors—glial cell line‐derived neurotrophic factor (GDNF), neurturin, persephin, and artemin—are the ligands of these multimolecular receptors in which the nature of the GFRα determines the ligand specificity of the complex [see Baloh et al., 1998, for references]. It is well documented that RET/GFRα‐1/GDNF delivers a signal critical for the survival of the early neural crest‐derived precursors that colonize the intestine below the rostral foregut and give rise to the enteric nervous plexuses [Gershon, 1997; Cacalano et al., 1998; Enomoto et al., 1998]. Hum Mutat 13:331–336, 1999. © 1999 Wiley‐Liss, Inc.