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Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?
Abstract:
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, GFRalpha((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 GFRalpha determines the ligand specificity of the complex [see Baloh et al., 1998, for references]. It is well documented that RET/GFRalpha-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].
Insights
Multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung's disease (HSCR) are inherited disorders caused by RET gene mutations. The RET receptor tyrosine kinase pathway is crucial for neural crest cell development, impacting both cancer syndromes and congenital malformations.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Oncology
Background:
- Multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung's disease (HSCR) are inherited neurocristopathies linked to RET gene mutations.
- MEN2 encompasses MEN type 2A, MEN type 2B, and familial MTC, characterized by endocrine tumors.
- HSCR is a congenital condition resulting from absent enteric plexuses, causing neonatal bowel obstruction.
Discussion:
- The RET gene encodes a receptor tyrosine kinase essential for the RET/GFRalpha signaling pathway.
- This pathway involves GFRalpha co-receptors and GDNF family ligands, determining signal specificity.
- The RET/GFRalpha-1/GDNF axis is vital for neural crest cell survival and enteric nervous system development.
Key Insights:
- Mutations in the RET gene underlie both MEN2 and HSCR, highlighting a shared genetic basis for these distinct neurocristopathies.
- The RET signaling pathway plays a critical role in the development of neural crest-derived cells, including those forming the enteric nervous system.
- Understanding the RET pathway's function is key to deciphering the pathogenesis of MEN2 and HSCR.
Outlook:
- Further research into the RET pathway could reveal novel therapeutic targets for MEN2 and HSCR.
- Investigating the precise mechanisms of RET signaling in neural crest development may offer insights into other neurocristopathies.
- Genetic counseling and early detection strategies for MEN2 and HSCR can be informed by a deeper understanding of RET gene mutations.