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[Neural crest and multiple endocrinopathies].
C R Seances Soc Biol Fil. 1996; 190(5-6):557-67.CR

Abstract

Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins.

Authors+Show Affiliations

Laboratoire de Génétique, UMR 5641, CNRS, Université Claude-Bernard Lyon I, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

English Abstract
Journal Article
Review

Language

fre

PubMed ID

9074721

Citation

Pasini, A, et al. "[Neural Crest and Multiple Endocrinopathies]." Comptes Rendus Des Seances De La Societe De Biologie Et De Ses Filiales, vol. 190, no. 5-6, 1996, pp. 557-67.
Pasini A, Michiels FM, Chappuis-Flament S, et al. [Neural crest and multiple endocrinopathies]. C R Seances Soc Biol Fil. 1996;190(5-6):557-67.
Pasini, A., Michiels, F. M., Chappuis-Flament, S., Geneste, O., Rossel, M., Fournier, L., Feunteun, J., Lenoir, G., Schuffenecker, I., & Billaud, M. (1996). [Neural crest and multiple endocrinopathies]. Comptes Rendus Des Seances De La Societe De Biologie Et De Ses Filiales, 190(5-6), 557-67.
Pasini A, et al. [Neural Crest and Multiple Endocrinopathies]. C R Seances Soc Biol Fil. 1996;190(5-6):557-67. PubMed PMID: 9074721.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - [Neural crest and multiple endocrinopathies]. AU - Pasini,A, AU - Michiels,F M, AU - Chappuis-Flament,S, AU - Geneste,O, AU - Rossel,M, AU - Fournier,L, AU - Feunteun,J, AU - Lenoir,G, AU - Schuffenecker,I, AU - Billaud,M, PY - 1996/1/1/pubmed PY - 1996/1/1/medline PY - 1996/1/1/entrez SP - 557 EP - 67 JF - Comptes rendus des seances de la Societe de biologie et de ses filiales JO - C R Seances Soc Biol Fil VL - 190 IS - 5-6 N2 - Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins. SN - 0037-9026 UR - https://www.unboundmedicine.com/medline/citation/9074721/[Neural_crest_and_multiple_endocrinopathies]_ DB - PRIME DP - Unbound Medicine ER -