Co-segregation of MEN2 and Hirschsprung's disease: The same mutation of RET with both gain and loss-of-function?

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, 199 7]. MEN2 is a cancer syndrome comprising three related clinical subtypes: ( 1) MEN type 2A (MEN2A; MIM# 171400) characterized by the association of med ullary thyroid carcinoma (MTC), pheochromocytoma (Pheo), and hyperparathyro idism; (2) MEN type 2B (MEN2B; MIM# 162300), which includes MTC, Pheo, muco sal neuromas, ganglioneuromatosis of the digestive tract, and skeletal abno rmalities; and (3) familial MTC (FMTC; MIM# 155240), defined by the sole oc currence of MTC. HSCR (MIM# 142623) is a congenital malformation caused by the absence of enteric plexuses in the hindgut, leading to bowel obstructio n in neonates. The RET gene (MIM# 164761) codes for a transmembrane tyrosin e kinase, a component of a multimeric complex that also comprises one of fo ur members of a novel family of glycosylphosphatidylinositol (GPI)-anchored receptor, GFR alpha(1-4) (e.g., GFRA1, MIM# 601496; references are detaile d in Baloh et al. [1998]. Four structurally related soluble factors-glial c ell line-derived neurotrophic factor (GDNF), neurturin, persephin, and arte min-are the ligands of these multimolecular receptors in which the nature o f the GFR alpha determines the ligand specificity of the complex [see Baloh et al., 1998, for references]. It is well documented that RET/GFR alpha-1/ GDNF delivers a signal critical for the survival of the early neural crest derived precursors that colonize the intestine below the rostral foregut an d give rise to the enteric nervous plexuses [Gershon, 1997; Cacalano et al. , 1998; Enomoto et al., 1998]. Hum Mutat 13:331-336, 1999. (C) 1999 Wiley L iss, Inc.