Mutation Analysis of the MEN1 Gene in Multiple Endocrine Neoplasia Type 1, Familial Acromegaly and Familial Isolated Hyperparathyroidism

Teh, Bin Tean

doi:10.1210/jc.83.8.2621

Cited by 106 publications

(117 citation statements)

References 20 publications

(31 reference statements)

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“…7 Among pedigrees strictly defined as having familial MEN1, we found mutations in 76.3%, which approaches the rates reported by others. 8,20,22,26,33,34 In pedigrees that do meet the diagnostic criteria for familial MEN1, a failure to find mutations in the MEN1 gene could reflect the presence of functionally significant intronic muta- Fig. 1.…”

Section: Discussionmentioning

confidence: 99%

Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory

Klein

Salih

Bessoni

et al. 2005

Genetics in Medicine

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Purpose: Based on results of diagnostic MEN1 testing, we have attempted to further define the mutational spectrum of the MEN1 gene and the clinical features most frequently associated with MEN1 mutations. Methods:Mutation testing was performed on blood samples by PCR amplification and sequencing of exons 2 to 10 of the MEN1 gene and the corresponding intron-exon junctions. Pedigree phenotypic information was obtained by written questionnaire. Results: Among 288 presumably unrelated pedigrees, 73 independent mutations were found in 89 families. Five mutations were found in 2 pedigrees, and 4 mutations were seen in more than 2 pedigrees. There were 17 nonsense mutations (23.3%), 2 in-frame deletions (2.7%), 18 frameshift-deletion mutations (24.7%), 10 frameshift-insertion or -duplication mutations (13.7%), 13 splice-site mutations (17.8%), and 13 presumptive

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Section: Discussionmentioning

confidence: 99%

Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory

Klein

Salih

Bessoni

et al. 2005

Genetics in Medicine

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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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“…Genetic analysis of one FIHP family (12) produced, though inconclusive (13), positive linkage results in the MEN1 region suggesting that it is a variant of MEN1. Mutation analysis conducted in subsequent studies, however, gave variable results (6,(14)(15)(16)(17)(18). We describe here a Japanese family with FIHP and evaluate their clinical, pathological and genetic profiles.…”

Section: Introductionmentioning

confidence: 96%

A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism

Honda

Tsukada²,

Tanaka³

et al. 2000

European Journal of Endocrinology

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Objective: To determine whether familial isolated hyperparathyroidism (FIHP) is a variant of multiple endocrine neoplasia type 1 (MEN1) we analyzed the MEN1 gene in such a kindred. Design and methods:The study included the 70-year-old proband and nine relatives. Blood was drawn for biochemical evaluation and germline mutation analysis by direct sequencing of the MEN1 gene amplified by PCR. A hyperplastic parathyroid gland obtained from a family member served for a loss of heterozygosity (LOH) study. Results: Three members from two generations in this kindred were found to have primary hyperparathyroidism, while none had clinical or biochemical evidence of MEN1, MEN2 or hyperparathyroidismjaw tumor syndrome. Analysis of germline DNA in the proband showed a missense mutation (GGC → GAC) at codon 305 in exon 7 of the MEN1 gene that predicts an amino acid change from glycine to aspartic acid (G305D). This mutation segregated with primary hyperparathyroidism in the kindred, and, in addition, there were two asymptomatic mutant-gene carriers at relatively advanced ages. In contrast, the mutation was not detected in genomic DNA from five unaffected individuals and from 50 healthy subjects. The LOH study showed a loss of the wild-type allele, which confirmed that a functional defect of the MEN1 gene product, menin, is etiological for FIHP. Conclusions: FIHP is a genetically heterogeneous disease with a subset linked to MEN1, most likely representing a variant of MEN1. The late onset and the reduced penetrance of disease found in this kindred may be related to the site and the type of mutation, although the precise mechanism involved is unknown at present.

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Mutation Analysis of the MEN1 Gene in Multiple Endocrine Neoplasia Type 1, Familial Acromegaly and Familial Isolated Hyperparathyroidism

Cited by 106 publications

References 20 publications

Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory

Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory

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

A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism

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