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Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms.
Cancer Sci. 2011 Nov; 102(11):2097-102.CS

Abstract

Germline mutations of the tumor suppressor gene MEN1 are found not only in typical multiple endocrine neoplasia type 1 (MEN1) but also in its incomplete forms such as familial isolated hyperparathyroidism (FIHP) and apparently sporadic parathyroid tumor (ASPT). No definitive genotype-phenotype correlation has been established between these clinical forms and MEN1 gene mutations. We previously demonstrated that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. To examine whether the intracellular stability of mutant menin is correlated with clinical phenotypes, we developed a method of evaluating menin stability and examined 20 mutants associated with typical MEN1 (17 missense, two in-frame deletion, one nonsense) and 21 mutants associated with FIHP or ASPT (19 missense, two in-frame deletion). All tested mutants associated with typical MEN1 showed reduced stability. Some missense and in-frame deletion mutants (G28A, R171W, T197I, E255K, E274A, Y353del and E366D) associated with FIHP or ASPT were almost as stable as or only slightly less stable than wild-type menin, while others were as unstable as those associated with typical MEN1. Some stable mutants exhibited substantial biological activities when tested by JunD-dependent transactivation assay. These findings suggest that certain missense and in-frame mutations are fairly stable and retain intrinsic biological activity, and might be specifically associated with incomplete clinical phenotypes. The menin stability test will provide useful information for the management of patients carrying germline MEN1 mutations especially when they have missense or in-frame variants of ambiguous clinical significance.

Authors+Show Affiliations

Division of Familial Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21819486

Citation

Shimazu, Satoko, et al. "Correlation of Mutant Menin Stability With Clinical Expression of Multiple Endocrine Neoplasia Type 1 and Its Incomplete Forms." Cancer Science, vol. 102, no. 11, 2011, pp. 2097-102.
Shimazu S, Nagamura Y, Yaguchi H, et al. Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. Cancer Sci. 2011;102(11):2097-102.
Shimazu, S., Nagamura, Y., Yaguchi, H., Ohkura, N., & Tsukada, T. (2011). Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. Cancer Science, 102(11), 2097-102. https://doi.org/10.1111/j.1349-7006.2011.02055.x
Shimazu S, et al. Correlation of Mutant Menin Stability With Clinical Expression of Multiple Endocrine Neoplasia Type 1 and Its Incomplete Forms. Cancer Sci. 2011;102(11):2097-102. PubMed PMID: 21819486.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. AU - Shimazu,Satoko, AU - Nagamura,Yuko, AU - Yaguchi,Hiroko, AU - Ohkura,Naganari, AU - Tsukada,Toshihiko, Y1 - 2011/09/01/ PY - 2011/8/9/entrez PY - 2011/8/9/pubmed PY - 2011/12/20/medline SP - 2097 EP - 102 JF - Cancer science JO - Cancer Sci VL - 102 IS - 11 N2 - Germline mutations of the tumor suppressor gene MEN1 are found not only in typical multiple endocrine neoplasia type 1 (MEN1) but also in its incomplete forms such as familial isolated hyperparathyroidism (FIHP) and apparently sporadic parathyroid tumor (ASPT). No definitive genotype-phenotype correlation has been established between these clinical forms and MEN1 gene mutations. We previously demonstrated that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. To examine whether the intracellular stability of mutant menin is correlated with clinical phenotypes, we developed a method of evaluating menin stability and examined 20 mutants associated with typical MEN1 (17 missense, two in-frame deletion, one nonsense) and 21 mutants associated with FIHP or ASPT (19 missense, two in-frame deletion). All tested mutants associated with typical MEN1 showed reduced stability. Some missense and in-frame deletion mutants (G28A, R171W, T197I, E255K, E274A, Y353del and E366D) associated with FIHP or ASPT were almost as stable as or only slightly less stable than wild-type menin, while others were as unstable as those associated with typical MEN1. Some stable mutants exhibited substantial biological activities when tested by JunD-dependent transactivation assay. These findings suggest that certain missense and in-frame mutations are fairly stable and retain intrinsic biological activity, and might be specifically associated with incomplete clinical phenotypes. The menin stability test will provide useful information for the management of patients carrying germline MEN1 mutations especially when they have missense or in-frame variants of ambiguous clinical significance. SN - 1349-7006 UR - https://www.unboundmedicine.com/medline/citation/21819486/Correlation_of_mutant_menin_stability_with_clinical_expression_of_multiple_endocrine_neoplasia_type_1_and_its_incomplete_forms_ L2 - https://doi.org/10.1111/j.1349-7006.2011.02055.x DB - PRIME DP - Unbound Medicine ER -