This report describes multiple endocrine neoplasia, type IIA (MEN2A), which is a subtype of multiple endocrine neoplasia; MEN2A exhibits autosomal dominant inheritance. The human gene implicated in this disease is RET, which encodes a receptor tyrosine kinase. A second subtype, multiple endocrine neoplasia, type IIB (MEN2B, FBhh0000014) is also caused by defects in the human RET gene; the RET gene is implicated in multiple other diseases (OMIM:164761), including medullary thyroid carcinoma (FBhh0000025). There is a single high-scoring fly ortholog, Dmel\Ret, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated.
A UAS construct of a wild human Hsap\RET gene has been introduced into flies. Thus far, it has served primarily as a control for experiments using human disease models based on the RET gene (this report, FBhh0000014, FBhh0000769).
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): C695R in the fly Ret gene (corresponds to C634R in the human RET gene; designated RetMEN2A.GMR, RetMEN2A.UAS and RetC695R.UAS).
UAS constructs with the Dmel\Ret gene carrying a mutation comparable to the most common lesion found in carriers of MEN2A have been introduced into flies. Using this system, potential interacting partners of Dmel\Ret have been identified in genetic screens. Results are consistent with upregulation of the SOS/Ras/ERK pathway as the key effector of MEN2 pathology; the Src and Jun kinase pathways also appear to play key roles.
Therapeutic drug candidates: using the MEN2A-analogous mutation of Dmel\Ret (C695R), specificity and dosage effects of a potential therapeutic agent have been assessed.
[updated Jun. 2019 by FlyBase; FBrf0222196]
Multiple endocrine neoplasias are characterized by varying combinations of tumors derived from endocrine glands, including parathyroid, thyroid, pituitary, and adrenal glands. Frequently the tumors are nonmetastasizing, but can cause serious clinical effects due to the inappropriate secretion of endocrine substances. [from OMIM:131100, OMIM:171400, OMIM:162300; 2014.07.03]
For additional information on classification and genetics see http://www.thyroidcancer.com/thyroid-cancer/medullary/genetics.
[MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; MEN2A](https://omim.org/entry/171400)
[REARRANGED DURING TRANSFECTION PROTOONCOGENE; RET](https://omim.org/entry/164761)
MEN2A is a syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma, pheochromocytoma [a tumor of the adrenal glands], and parathyroid adenomas. Medullary carcinoma of the thyroid is the most consistent single manifestation of this disorder and occurs in almost all cases by age 40. [from OMIM:171400; 2015.02.16]
MEN2A patients have a less virulent form of medullary thyroid carcinoma than do MEN2B patients. In MEN2A patients, 50% of those with RET gene mutations develop the disease by age 50 years, and 70% develop the disease by age 70 years. [from Medscape, Type 2 Multiple Endocrine Neoplasia, 2014.08.26]
MEN2A is inherited as an autosomal dominant mapping to the RET gene. [from OMIM:171400; 2015.02.16]
MEN2 syndromes are relatively rare; the overall frequency in the United States is 1 case per 30,000-50,000 persons. In decreasing order of frequency, MEN2 occurs as follows: MEN2A, FMTC only, and MEN2B. [from Medscape, Type 2 Multiple Endocrine Neoplasia; 2014.08.26]
RET is a receptor tyrosine kinase of the cadherin superfamily. Other diseases associated with mutations in the RET gene include multiple endocrine neoplasia, type IIB (MEN2B; 162300), Hirschsprung disease (HSCR; aganglionic megacolon; 142623), and medullary thyroid carcinoma (MTC; 155240).[from OMIM:164761; 2015.02.16]
Mutations that have been identified as causing heritable MEN2A are primarily point mutations in a cysteine-rich extracellular domain and result in constitutive (ligand-independent) dimerization and activation. Substitutions of cysteines within the extracellular domain are found in up to 95% of cases; this leads to an unpaired reactive cysteine.