<i>MEN1</i> gene mutations in Hungarian patients with multiple endocrine neoplasia type 1

Balogh, Katalin; Hunyady, László; Patócs, Attila; Gergics, Péter; Valkusz, Z.; Tóth, Miklós; Rácz, Kàroly

doi:10.1111/j.1365-2265.2007.02953.x

Cited by 23 publications

(18 citation statements)

References 33 publications

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“…The mouse menin cDNA was obtained by PCR amplification using a spleen cDNA library as the template as previously described. (15) The previously reported variant sequences and their corresponding phenotypes were according to the references as follows: P12L, L22R, K119del, H139D, A160P, A242V, A309P, T344R, E363del, W436R and R460X; (16) G28A; (17) D153V and A411P; (18) G156C, F364C and F447L; (19) A160T and D418N; (20) R171W and E366D; (21) V184E; (9) T197I and Y353del; (22) W220L and Y351N; (23) R229L; (24) S253W and E274A; (11) E255K; (10) Q260P; (25) L264P and L267P; (26) P277H; (27) G305D; (12) H317Y; (14) P320R; (28) P320L; (29) L414del; (30) and S555N. (31) The expression vector pCMV-BICEP-4 (Sigma, St. Louis, MO, USA), designed to allow translation of two proteins from one bicistronic mRNA, was used for transient co-expression of N-terminal FLAG-tagged and Myc-tagged menin proteins.…”

Section: Methodsmentioning

confidence: 99%

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Shimazu¹,

Nagamura²,

Yaguchi

et al. 2011

Cancer Science

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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. (Cancer Sci 2011; 102: 2097-2102 M enin is a tumor suppressor protein encoded by MEN1, a gene responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome typically characterized by the development of multiple tumors in the pituitary, parathyroid and enteropancreatic endocrine tissues.(1,2) Menin is a nuclear protein having C-terminal nuclear localizing signal sequences, (3) and exhibits modulatory activity on gene expression such as repression of JunD-dependent transcription. (4) Diverse roles have been implicated for menin, including cell cycle control, cell differentiation and DNA repair, which are likely to be conferred by interaction with various menin-binding proteins.(2) Menin is considered to be a scaffold protein tethering such proteins to specific gene loci.(5) Although the mechanism of how menin is involved in gene regulation has been elucidated to some extent, the basis for tissue-specific tumorigenesis in MEN1 remains unknown.Heterozygous germline mutations of the MEN1 gene are found in 70-90% of patients clinically diagnosed as MEN1. (6) More than 500 different loss-of-function mutations have been identified, which are distributed throughout the gene with no apparent hot spot.(2,6,7) Germline MEN1 mutations have also been found in a subset of familial isolated hyperparathy...

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Section: Methodsmentioning

confidence: 99%

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Shimazu¹,

Nagamura²,

Yaguchi

et al. 2011

Cancer Science

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“…As detailed in other studies presenting Hungarian data on mutation analysis of MEN1, RET and CaSR [44][45][46], familial forms of PHPT and hypercalcemic conditions resulting from CaSR mutations represent only a small fraction of patients with PHPT.…”

Section: Relative Frequencies Of Sporadic and Hereditary Forms Of Phptmentioning

confidence: 99%

Parathyroid hormone-dependent hypercalcemia

Tőke

Patócs

Balogh

et al. 2009

Wien Klin Wochenschr

Self Cite

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The past fifteen years have resulted in great progress in our understanding of the pathogenesis and pathophysiology of hypercalcemic disorders occurring either sporadically or in a familial setting. This paper briefly reviews the clinically most important new knowledge on sporadic and hereditary forms of parathyroid hormone-dependent hypercalcemic disorders, with special emphasis on familial syndromes such as multiple endocrine neoplasia type 1 and type 2A, hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism. In addition, the authors briefly present the most important clinical characteristics of 141 patients with parathyroid hormone-dependent hypercalcemia, including index patients of 18 families with hereditary disorders, diagnosed in a Hungarian endocrine center between 1997 and 2007.

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“…A mutáci-ókra jellemző, hogy minden család egyedi mutációt hordozott, nem igazolódott alapító mutáció a hazai beteganyagban. A mutációk többsége stop kodont vagy kereteltolódást okozó rövid deletio vagy inszerció volt [7]. A genotípus-fenotípus összefüggések során a betegekben mindhárom fő manifesztáció kb.…”

Section: Men1-szindrómaunclassified

Molekuláris genetikai vizsgálatok az örökletes endokrinológiai tumor szindrómák klinikai diagnosztikájában

et al. 2018

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Az örökletes endokrinológiai tumor szindrómák, vagy multiplex endokrin neoplasiák (MEN) közös jellegzetességei a különböző endokrin szervek daganatainak társulása egy betegben vagy egy családon belül. A MEN-szindrómáknak több altípusát különböztethetjük meg, amelyek közül az 1-es és a 2-es típus a leggyakoribb. Öröklődésük az autoszomális domináns jelleget követi, az érintett családokban 50%-os az átörökítés valószínűsége. A MEN-szindrómák mellett a sporadikus megjelenésű endokrin daganatok genetikai hátterében is igazolhatók a MEN-szindrómákért felelős gének eltérései, és a később MEN-szindrómásnak bizonyuló esetek zöme is sporadikus formaként kerül felismerésre. A molekuláris genetikai diagnosztika elsődleges szerepe ezekben a szindrómákban a betegségért felelős eltérés kimutatása, majd genetikai tanácsadást követően az érintett családokban genetikai szűrővizsgálatok végzése. A vizsgálat után a tünetmentes, de a mutációit hordozó egyének folyamatos klinikai nyomon követésével a daganatok morbiditásának megelőzése, csökkenése érhető el. Az utóbbi évek technológiai fejlődésével átalakult az örökletes kórképek molekuláris genetikai diagnosztikája is. Az új generációs szekvenálásnak a klinikai munkában történő elterjedésével az endokrindaganat-szindrómákban is bővült a vizsgálandó gének száma. A jelen összefoglalóban áttekint-jük az örökletes endokrin tumor szindrómák genetikai hátterét, és bemutatjuk a jelenleg is alkalmazott molekuláris biológiai vizsgálómódszereket. Orv Hetil. 2018; 159(7): 285-292.

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MEN1 gene mutations in Hungarian patients with multiple endocrine neoplasia type 1

Abstract: These results confirm previous reports on the high prevalence of novel MEN1 gene mutations among patients with MEN1, and support the questionable efficacy of mutation screening in patients with sporadic MEN1-related states.

Cited by 23 publications

References 33 publications

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Parathyroid hormone-dependent hypercalcemia

Molekuláris genetikai vizsgálatok az örökletes endokrinológiai tumor szindrómák klinikai diagnosztikájában

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