Novel V184EMEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism

Fujimori, Minoru; Shirahama, Shuya; Sakurai, Akihiro; Hashizume, Kiyoshi; Hama, Yoshihisa; Ito, Kenichi; Shingu, Kiyoshi; Kobayashi, Shinya; Amano, Jun; Fukushima, Yoshimitsu

doi:10.1002/(sici)1096-8628(19981116)80:3<221::aid-ajmg8>3.0.co;2-1

Cited by 40 publications

(30 citation statements)

References 7 publications

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“…frameshift mutations leading to a premature protein truncation) have been found in its proximity in the 3 moiety of exon 2 (Chandrasekharappa et al 1997). After initial negative reports (Tanaka et al 1998), other families with fiHP and MEN1 germ line mutations have been described , Fujimori et al 1998.…”

Section: Discussionmentioning

confidence: 99%

Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region

Karges

Jostarndt²,

Maier³

et al. 2000

Journal of Endocrinology

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Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR singlestrand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19·3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5 region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9·6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.

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Section: Discussionmentioning

confidence: 99%

Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region

Karges

Jostarndt²,

Maier³

et al. 2000

Journal of Endocrinology

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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%

“…(2,6,7) Germline MEN1 mutations have also been found in a subset of familial isolated hyperparathyroidism (FIHP), (8)(9)(10) defined as familial primary hyperparathyroidism not associated with other diseases, and in a few patients clinically diagnosed as having sporadic parathyroid tumor.…”

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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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“…To determine the clinical relevance of the menin-ERa interaction, 11 disease-related MEN1 mutants were tested in the yeast two-hybrid assay. These mutations have all been reported in the literature (25)(26)(27)(28)(29)(30). Most mutations disrupted the liganddependent interaction between menin and ERa (Fig.…”

Section: Cancer Researchmentioning

confidence: 99%

Menin Links Estrogen Receptor Activation to Histone H3K4 Trimethylation

Dreijerink¹,

Mulder²,

Winkler³

et al. 2006

Cancer Research

185

179

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The product of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, menin, is an integral component of MLL1/MLL2 histone methyltransferase complexes specific for Lys4 of histone H3 (H3K4). We show that menin is a transcriptional coactivator of the nuclear receptors for estrogen and vitamin D. Activation of the endogenous estrogen-responsive TFF1 (pS2) gene results in promoter recruitment of menin and in elevated trimethylation of H3K4. Knockdown of menin reduces both activated TFF1 (pS2) transcription and H3K4 trimethylation. In addition, menin can directly interact with the estrogen receptor-A (ERA) in a hormone-dependent manner. The majority of disease-related MEN1 mutations prevent menin-ERA interaction. Importantly, ERA-interacting mutants are also defective in coactivator function. Our results indicate that menin is a critical link between recruitment of histone methyltransferase complexes and nuclear receptor-mediated transcription. (Cancer Res 2006; 66(9): 4929-35)

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Novel V184EMEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism

Cited by 40 publications

References 7 publications

Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region

Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region

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

Menin Links Estrogen Receptor Activation to Histone H3K4 Trimethylation

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