Clinical Testing for Mutations in the<i>MEN1</i>Gene in Sweden: A Report on 200 Unrelated Cases

Tham, Emma; Grandell, Ulla; Lindgren, Eva; Toss, Göran; Skogseid, Britt; Nordenskjöld, Magnus

doi:10.1210/jc.2007-0476

Cited by 107 publications

(108 citation statements)

References 28 publications

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“…It is well accepted that pediatric MEN1 patients usually present fewer MEN1-related tumors than adults. However, as observed in our patient cohort and in others reported previously, the full manifestation of the disease (with the development of all four of the main MEN1-related tumors) does not occur in every adult patient older than 30 years (9,10,19,20,22,23,24,25). In fact, we found that age was not a risk factor for developing multiple tumors in three or four glands among our patients aged 30 years or more (PZ0.70).…”

Section: Phenotypic Modulation Of Rs2066827 In Men1 Overall Cohortsupporting

confidence: 81%

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

Longuini

Lourenço

Sekiya

et al. 2014

European Journal of Endocrinology

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Objective: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for. Design: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. Methods: Genotyping of the coding p27 c.326TOG (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression. Results: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (ORZ2.55, PZ0.019, CIZ1.013-5.76). Among patients who are R30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; ORZ18.33; PZ0.002, CIZ2. 88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors. European Journal of EndocrinologyClinical Study V C Longuini and others p27 rs2066827, an MEN1 syndrome modifier

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Section: Phenotypic Modulation Of Rs2066827 In Men1 Overall Cohortsupporting

confidence: 81%

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

Longuini

Lourenço

Sekiya

et al. 2014

European Journal of Endocrinology

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“…(2,3) Since then, approximately 500 different germline mutations that cause loss of MEN1 gene function have been identified in patients with MEN1 and related disorders. (4)(5)(6)(7)(8)(9)(10) The germline mutations are heterozygous, and somatic loss of the normal MEN1 allele has been observed in the tumors arising in MEN1, in agreement with the Knudson's two-hit model. (11) Somatic inactivation of both MEN1 alleles has also been detected in some sporadic endocrine tumors, indicating involvement of this gene in the development of sporadic tumors.…”

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confidence: 73%

MEN1 gene and its mutations: Basic and clinical implications

Tsukada¹,

Nagamura²,

Ohkura³

2009

Cancer Science

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Heterozygous germline mutations of the tumor-suppressor gene MEN1 are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited familial cancer syndrome characterized by pituitary, parathyroid, and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and related disorders. Neither mutation hot spot nor phenotype-genotype correlation has been established in MEN1 although some missense mutations may be specifically associated with a phenotype of familial isolated hyperparathyroidism. The gene product menin has been implicated in multiple roles, including gene transcription, maintenance of genomic integrity, and control of cell division and differentiation. These multiple functions are likely to be conferred by association with multiple protein factors. Occurrence of MEN1-causing missense mutations throughout menin also suggests the requirement of multiple binding factors for its full tumor-suppressive activity. The effect of menin depletion is highly tissue specific, but its underlying mechanism remains to be elucidated. A DNA test for MEN1 germline mutations is a useful tool for diagnosis of MEN1 although it needs further improvements. The germline mutations are heterozygous, and somatic loss of the normal MEN1 allele has been observed in the tumors arising in MEN1, in agreement with the Knudson's two-hit model. (11) Somatic inactivation of both MEN1 alleles has also been detected in some sporadic endocrine tumors, indicating involvement of this gene in the development of sporadic tumors. So far, MEN1 gene mutations have not been implicated in any other human diseases.The product of the MEN1 gene, menin, is a 610-amino acid protein that exhibits no apparent sequence similarity to any other known protein.(1) Thus, its biochemical function can not be deduced from its structure. In the last decade, a number of studies have demonstrated physical and functional associations between menin and diverse proteins of known function, shedding light on its molecular function. These menin-interacting proteins include nuclear proteins such as transcription factors, histone deacetylases, and histone methyltransferases, suggesting that menin is involved in gene transcription. Several lines of evidence also suggest that menin is involved in the maintenance of genomic integrity. Although menin is localized mainly to cell nuclei, possible extranuclear functions have not been excluded because various cytoplasmic proteins bind to menin.Although the molecular function of menin is still poorly understood, identification of the MEN1 gene has enabled a direct DNA test for predisposition to MEN1. In the present review, recent findings on the MEN1 gene are summarized and its mutations are discussed from basic and clinical points of view. Structure and expression of the MEN1 geneThe human MEN1 gene comprises 10 exons distributed over 7 kb in the chromosome region 11q13 and encodes mRNA of approximately 2.8 kb (Fig. 2).(1) Exons 2 through 10 encode th...

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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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Clinical Testing for Mutations in theMEN1Gene in Sweden: A Report on 200 Unrelated Cases

Cited by 107 publications

References 28 publications

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

MEN1 gene and its mutations: Basic and clinical implications

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

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