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Science 18 April 1997:
Vol. 276. no. 5311, pp. 404 - 407
DOI: 10.1126/science.276.5311.404
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Reports

Positional Cloning of the Gene for Multiple Endocrine Neoplasia-Type 1 

Settara C. Chandrasekharappa, Siradanahalli C. Guru, Pachiappan Manickam, Shodimu-Emmanuel Olufemi, Francis S. Collins, * Michael R. Emmert-Buck, Larisa V. Debelenko, Zhengping Zhuang, Irina A. Lubensky, Lance A. Liotta , Judy S. Crabtree, Yingping Wang, Bruce A. Roe, Jane Weisemann, Mark S. Boguski , Sunita K. Agarwal, Mary Beth Kester, Young S. Kim, Christina Heppner, Qihan Dong, dagger Allen M. Spiegel, A. Lee Burns, Stephen J. Marx

Multiple endocrine neoplasia-type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by tumors in parathyroids, enteropancreatic endocrine tissues, and the anterior pituitary. DNA sequencing from a previously identified minimal interval on chromosome 11q13 identified several candidate genes, one of which contained 12 different frameshift, nonsense, missense, and in-frame deletion mutations in 14 probands from 15 families. The MEN1 gene contains 10 exons and encodes a ubiquitously expressed 2.8-kilobase transcript. The predicted 610-amino acid protein product, termed menin, exhibits no apparent similarities to any previously known proteins. The identification of MEN1 will enable improved understanding of the mechanism of endocrine tumorigenesis and should facilitate early diagnosis.

S. C. Chandrasekharappa, S. C. Guru, P. Manickam, S.-E. Olufemi, F. S. Collins, Laboratory of Gene Transfer, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
M. R. Emmert-Buck, L. V. Debelenko, Z. Zhuang, I. A. Lubensky, L. A. Liotta, Laboratory of Pathology, National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
J. S. Crabtree, Y. Wang, B. A. Roe, Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
J. Weisemann and M. S. Boguski, National Center for Biotechnology Information, National Library of Medicine (NLM), NIH, Bethesda, MD 20894, USA.
S. K. Agarwal, M. B. Kester, Y. S. Kim, C. Heppner, Q. Dong, A. M. Spiegel, A. L. Burns, S. J. Marx, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD 20892, USA.
*   To whom correspondence should be addressed. E-mail: fc23a{at}nih.gov

dagger    Present address: Department of Medicine, University of Sydney, Sydney NSW 2006, Australia.

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   Abstract »    Full Text »    PDF »
Leukemia Proto-Oncoprotein MLL Forms a SET1-Like Histone Methyltransferase Complex with Menin To Regulate Hox Gene Expression.
A. Yokoyama, Z. Wang, J. Wysocka, M. Sanyal, D. J. Aufiero, I. Kitabayashi, W. Herr, and M. L. Cleary (2004)
Mol. Cell. Biol. 24, 5639-5649
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BLAST: at the core of a powerful and diverse set of sequence analysis tools.
S. McGinnis and T. L. Madden (2004)
Nucleic Acids Res. 32, W20-W25
   Abstract »    Full Text »    PDF »
Tumor Suppressor Menin Regulates Expression of Insulin-Like Growth Factor Binding Protein 2.
P. La, R. W. Schnepp, C. D. Petersen, A. C. Silva, and X. Hua (2004)
Endocrinology 145, 3443-3450
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Transfection of the Multiple Endocrine Neoplasia Type 1 Gene to a Human Endocrine Pancreatic Tumor Cell Line Inhibits Cell Growth and Affects Expression of JunD, {delta}-Like Protein 1/Preadipocyte Factor-1, Proliferating Cell Nuclear Antigen, and QM/Jif-1.
P. Stalberg, P. Grimfjard, M. Santesson, Y. Zhou, D. Lindberg, A. Gobl, K. Oberg, G. Westin, J. Rastad, S. Wang, et al. (2004)
J. Clin. Endocrinol. Metab. 89, 2326-2337
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Conditional Inactivation of the Men1 Gene Leads to Pancreatic and Pituitary Tumorigenesis but Does Not Affect Normal Development of These Tissues.
C. A. Biondi, M. G. Gartside, P. Waring, K. A. Loffler, M. S. Stark, M. A. Magnuson, G. F. Kay, and N. K. Hayward (2004)
Mol. Cell. Biol. 24, 3125-3131
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Non-Islet Origin of Pancreatic Islet Cell Tumors.
A. O. Vortmeyer, S. Huang, I. Lubensky, and Z. Zhuang (2004)
J. Clin. Endocrinol. Metab. 89, 1934-1938
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Menin Inactivation Leads to Loss of Transforming Growth Factor {beta} Inhibition of Parathyroid Cell Proliferation and Parathyroid Hormone Secretion.
H. Sowa, H. Kaji, R. Kitazawa, S. Kitazawa, T. Tsukamoto, S. Yano, T. Tsukada, L. Canaff, G. N. Hendy, T. Sugimoto, et al. (2004)
Cancer Res. 64, 2222-2228
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Menin Induces Apoptosis in Murine Embryonic Fibroblasts.
R. W. Schnepp, H. Mao, S. M. Sykes, W.-X. Zong, A. Silva, P. La, and X. Hua (2004)
J. Biol. Chem. 279, 10685-10691
   Abstract »    Full Text »    PDF »
Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications.
J Warner, M Epstein, A Sweet, D Singh, J Burgess, S Stranks, P Hill, D Perry-Keene, D Learoyd, B Robinson, et al. (2004)
J. Med. Genet. 41, 155-160
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Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP).
A Villablanca, A Calender, L Forsberg, A Hoog, J-D Cheng, D Petillo, C Bauters, K Kahnoski, T Ebeling, P Salmela, et al. (2004)
J. Med. Genet. 41, e32-32
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Familial Isolated Hyperparathyroidism Is Rarely Caused by Germline Mutation in HRPT2, the Gene for the Hyperparathyroidism-Jaw Tumor Syndrome.
W. F. Simonds, C. M. Robbins, S. K. Agarwal, G. N. Hendy, J. D. Carpten, and S. J. Marx (2004)
J. Clin. Endocrinol. Metab. 89, 96-102
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Parathyroid Gland-specific Deletion of the Mouse Men1 Gene Results in Parathyroid Neoplasia and Hypercalcemic Hyperparathyroidism.
S. K. Libutti, J. S. Crabtree, D. Lorang, A. L. Burns, C. Mazzanti, S. M. Hewitt, S. O'Connor, J. M. Ward, M. R. Emmert-Buck, A. Remaley, et al. (2003)
Cancer Res. 63, 8022-8028
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Evidence for a Familial Esophageal Cancer Susceptibility Gene on Chromosome 13.
N. Hu, A. M. Goldstein, P. S. Albert, C. Giffen, Z.-Z. Tang, T. Ding, P. R. Taylor, and M. R. Emmert-Buck (2003)
Cancer Epidemiol. Biomarkers Prev. 12, 1112-1115
   Abstract »    Full Text »    PDF »
Genetics of Pituitary Tumors: Focus on G-Protein Mutations.
A. Lania, G. Mantovani, and A. Spada (2003)
Experimental Biology and Medicine 228, 1004-1017
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Menin, a Tumor Suppressor, Represses JunD-Mediated Transcriptional Activity by Association with an mSin3A-Histone Deacetylase Complex.
H. Kim, J.-E. Lee, E.-J. Cho, J. O. Liu, and H.-D. Youn (2003)
Cancer Res. 63, 6135-6139
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Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter.
S. K. Agarwal, E. A. Novotny, J. S. Crabtree, J. B. Weitzman, M. Yaniv, A. L. Burns, S. C. Chandrasekharappa, F. S. Collins, A. M. Spiegel, and S. J. Marx (2003)
PNAS 100, 10770-10775
   Abstract »    Full Text »    PDF »
Of Mice and MEN1: Insulinomas in a Conditional Mouse Knockout.
J. S. Crabtree, P. C. Scacheri, J. M. Ward, S. R. McNally, G. P. Swain, C. Montagna, J. H. Hager, D. Hanahan, H. Edlund, M. A. Magnuson, et al. (2003)
Mol. Cell. Biol. 23, 6075-6085
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Heterozygous Men1 Mutant Mice Develop a Range of Endocrine Tumors Mimicking Multiple Endocrine Neoplasia Type 1.
P. Bertolino, W.-M. Tong, D. Galendo, Z.-Q. Wang, and C.-X. Zhang (2003)
Mol. Endocrinol. 17, 1880-1892
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HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours.
V M Howell, C J Haven, K Kahnoski, S K Khoo, D Petillo, J Chen, G J Fleuren, B G Robinson, L W Delbridge, J Philips, et al. (2003)
J. Med. Genet. 40, 657-663
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Pancreatic {beta}-Cell-specific Ablation of the Multiple Endocrine Neoplasia Type 1 (MEN1) Gene Causes Full Penetrance of Insulinoma Development in Mice.
P. Bertolino, W.-M. Tong, P. L. Herrera, H. Casse, C. X. Zhang, and Z.-Q. Wang (2003)
Cancer Res. 63, 4836-4841
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Transcription Regulation of the Multiple Endocrine Neoplasia Type 1 Gene in Human and Mouse.
B. Zablewska, L. Bylund, S. A. Mandic, M. Fromaget, P. Gaudray, and G. Weber (2003)
J. Clin. Endocrinol. Metab. 88, 3845-3851
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In Situ Analysis of Human Menin in Normal and Neoplastic Pancreatic Tissues: Evidence for Differential Expression in Exocrine and Endocrine Cells.
I. Cavallari, D. M. D'Agostino, T. Ferro, A. Rosato, L. Barzon, C. Pasquali, P. Fogar, M. Theodoropoulou, G. Esposito, M. Boscaro, et al. (2003)
J. Clin. Endocrinol. Metab. 88, 3893-3901
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Menin Associates with FANCD2, a Protein Involved in Repair of DNA Damage.
S. Jin, H. Mao, R. W. Schnepp, S. M. Sykes, A. C. Silva, A. D. D'Andrea, and X. Hua (2003)
Cancer Res. 63, 4204-4210
   Abstract »    Full Text »    PDF »
Mutational and gross deletion study of the MEN1 gene and correlation with clinical features in Spanish patients.
A Cebrian, S Ruiz-Llorente, A Cascon, M Pollan, J J Diez, A Pico, D Telleria, J Benitez, and M Robledo (2003)
J. Med. Genet. 40, e72-72
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Analysis of Microsatellite Instability in Sporadic Parathyroid Adenomas.
S. M. Mallya, J. J. Gallagher, and A. Arnold (2003)
J. Clin. Endocrinol. Metab. 88, 1248-1251
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The 32-Kilodalton Subunit of Replication Protein A Interacts with Menin, the Product of the MEN1 Tumor Suppressor Gene.
K. E. Sukhodolets, A. B. Hickman, S. K. Agarwal, M. V. Sukhodolets, V. H. Obungu, E. A. Novotny, J. S. Crabtree, S. C. Chandrasekharappa, F. S. Collins, A. M. Spiegel, et al. (2003)
Mol. Cell. Biol. 23, 493-509
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PRKAR1A, one of the Carney complex genes, and its locus (17q22-24) are rarely altered in pituitary tumours outside the Carney complex.
F Sandrini, L S Kirschner, T Bei, C Farmakidis, J Yasufuku-Takano, K Takano, T R Prezant, S J Marx, W E Farrell, R N Clayton, et al. (2002)
J. Med. Genet. 39, e78-78
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Menin, the Multiple Endocrine Neoplasia Type 1 Gene Product, Exhibits GTP-hydrolyzing Activity in the Presence of the Tumor Metastasis Suppressor nm23.
H. Yaguchi, N. Ohkura, T. Tsukada, and K. Yamaguchi (2002)
J. Biol. Chem. 277, 38197-38204
   Abstract »    Full Text »    PDF »


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