This report describes multiple endocrine neoplasia, type IIB (MEN2B), which is a subtype of multiple endocrine neoplasia; MEN2B 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 IIA (MEN2A, FBhh0000013) is also caused by defects in the human RET gene; the RET gene is implicated in multiple other diseases (MIM: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, FBhh0000013, FBhh0000769).
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): M955T in the fly Ret gene (corresponds to M918T in the human RET gene; designated RetMEN2B.GMR and RetMEN2B.UAS).
UAS constructs with the Dmel\Ret gene carrying a mutation comparable to the most common lesion found in carriers of MEN2B 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 MEN2B-analogous mutation of Dmel\Ret (M955T), a quantitative viability assay has been developed and has allowed efficient identification of potential therapeutic agents and testing of targeted modifications of candidate therapeutic compounds.
[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 MIM:131100, MIM:171400, MIM:162300; 2014.07.03]
For additional information on classification and genetics see http://www.thyroidcancer.com/thyroid-cancer/medullary/genetics.
[MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB; MEN2B](https://omim.org/entry/162300)
[RET PROTOONCOGENE; RET](https://omim.org/entry/164761)
MEN2B patients have a more virulent form of medullary thyroid carcinoma than do MEN2A patients. There have been cases of medullary thyroid carcinoma detected shortly after birth in MEN2B. [from Medscape, Type 2 Multiple Endocrine Neoplasia; 2014.08.26]
MEN2B is commonly characterized by aggressive medullary thyroid carcinoma; other cancers such as neuromas and pheochromocytoma [a tumor of the adrenal glands] may occur. Most affected individuals have characteristic physical features, including full lips, thickened eyelids, high-arched palate, and marfanoid habitus [symptoms resembling those of Marfan syndrome] (review by Morrison and Nevin, 1996, pubmed:8880581). [from MIM:162300; 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]
Approximately 50% of MEN2B cases arise from de novo germline mutations, primarily paternal in origin.
MEN2B is inherited as an autosomal dominant; it is caused by mutations in the RET gene. Most patients carry a specific M918T mutation, within the C-terminal cytoplasmic tyrosine kinase domain. [from MIM:162300 and MIM:164761; 2015.02.16]
RET is a receptor tyrosine kinase of the cadherin superfamily. Other diseases associated with mutations in the RET gene include multiple endocrine neoplasia, type IIA (MEN2A; 171400), Hirschsprung disease (HSCR; aganglionic megacolon; 142623), and medullary thyroid carcinoma (MTC; 155240). [from MIM:164761; 2015.02.16]
Mutations that have been identified as causing heritable MEN2B are primarily point mutations in the intracellular kinase domain and result in constitutive kinase activity. The most common mutations are M918T and A883F; these two specific mutations are also frequently found in sporadic medullary thyroid carcinoma.
One to one: 1 human to 1 Drosophila.
Ortholog of human RET (1 Drosophila to 1 human; additional more distantly related gene(s) in both species). Dmel\Ret shares 30% identity and 43% similarity with human RET.
