Abstract
Following identification of the MEN1 gene, we analysed patients from 12 MEN 1 families, 8 sporadic cases of MEN 1, and 13 patients with MEN 1-like symptoms (e.g. cases of familial isolated hyperparathyroidism (FIHPT), familial acromegaly, or atypical MEN 1 cases) for the presence of germline MEN1 mutations. The entire coding region of the MEN1 gene was sequenced, and mutations were detected in 11 MEN 1 families; one sporadic MEN 1 patient, one case of FIHPT and one MEN 1-like case. Constitutional DNA samples from individuals without MEN1 mutations were digested with several restriction enzymes, Southern blotted and probed with MEN1 cDNA to analyse for the presence of larger deletions of the MEN1 gene unable to be detected by PCR. One MEN 1 patient was found to carry such a deletion. This patient was heterozygous for the D418D polymorphism, however sequence analysis of RT-PCR products showed that only the variant allele was transcribed, thus confirming the result obtained by Southern analysis, which indicated loss of a region containing the initiation codon of one allele. © 2000 Cancer Research Campaign
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Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC, Doppman JL, Kim YS, Lubensky IA, Zhuang Z, Green JS, Guru SC, Manickam P, Olufemi S-E, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL and Marx SJ (1997) Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia and related states. Hum Mol Genet 6: 1169–1175
Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ and Burns AL (1999) Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 96: 143–152
Bassett JHD, Forbes SA, Pannett AAJ, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JAH, Wheeler MH and Thakker RV (1998) Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 62: 232–244
Chandrasekharappa SC, Guru SC, Manickam P, Olufemi S-E, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL and Marx SJ (1997) Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276: 404–407
Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM and Turner M (1997) Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol 133: 853–857
Engelbach M, Forst T, Hankeln T, Tratzky M, Heerdt S, Pfutzner A, Kann P, Kunt T, Schneider S, Schmidt ER and Beyer J (1999) Germline mutations in the MEN1 gene:creation of a new splice acceptor site and insertion of 7 intron nucleotides into the mRNA. Int J Mol Med 4: 483–485
Fujimori M, Shirahama S, Sakurai A, Hashizume K, Hama Y, Ito K, Shingu K, Kobayashi S, Amano J and Fukushima Y (1998) Novel V184E germline mutation in a Japanese kindred with familial hyperparathyroidism. Am J Med Genet 80: 221–222
Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert J-P, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou J-P, Guichard S, Rodier M, Meyrier A, Caron P, Vantyghem M-C, Assayag M, Peix J-L, Pugeat M, Rohmer V, Valloton M, Lenior G, Gaudray P, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar D, Murat A and Calender A (1998) Germ line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet 63: 455–467
Kishi M, Tsukada T, Shimizu S, Futami H, Ho Y, Kanbe M, Obara T and Yamaguchi K (1998) A large germline deletion of the MEN1 gene in a family with multiple endocrine neoplasia type 1. Japan J Cancer Res 81: 1–5
Komminoth P, Heitz PU and Klöppel G (1998) Pathology of MEN 1:morphology, clinicopathologic correlations and tumour development. J Intern Med 243: 455–464
Larsson C, Skogseid B, Öberg K, Nakamura Y and Nordenskjöld M (1988) Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332: 85–87
Lemmens I, Van de Ven WJM, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J, Lenoir G, Pugeat M, Calender A, Parente F, Quincey D, Gaudray P, De Wit MJ, Lips CJM, Höppener JWM, Khodaei S, Grant AL, Weber G, Kytölä S, Teh BT, Farnebo F, Phelan C, Hayward N, Larsson C, Pannett AAJ, Forbes SA, Bassett JHD and Thakker RV (1997) Identification of the multiple endocrine neoplasia type 1 (MEN 1) gene. Hum Mol Genet 6: 1177–1183
Miller SA, Dykes DD and Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 16: 1215
Ohye H, Sato M, Matsubara S, Miyauchi A, Imachi H, Murao K and Takahara J (1998) Germline mutation of the multiple endocrine neoplasia type 1 (MEN 1) gene in a family with primary hyperparathyroidism. Endocrine J 45: 719–723
Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ, Verloes A, Meurisse M, Van Gaal L, Verellen C, Koulischer L and Beckers A (1999) Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. Hum Mutat 13: 54–60
Sambrook J, Fritsch EF and Maniatis T (1989). Molecular Cloning: A Laboratory Manual, 2nd Ed, Cold Spring Harbour Laboratory Press: USA
Shimizu S, Tsukada T, Futami H, Ui K, Kameya T, Kawanaka M, Uchiyama S, Aoki A, Yasuda H, Kawano S, Ito Y, Kanbe M, Obara T and Yamaguchi K (1997) Germline mutation of the MEN1 gene in Japanese Kindred with multiple endocrine neoplasia type 1. Japan J Cancer Res 88: 1029–1032
Teh BT, Grimmond S, Shepherd J, Larsson C and Hayward N (1995) Multiple endocrine neoplasia type 1: clinical syndrome to molecular genetics. Aust NZ J Surg 65: 708–713
Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G, Hayward N, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjærg L, Jorde R, Menon J, Khir A, Tan TT, Chan SP, Zaini A, Khalid BAK, Sandelin K, Thompson N, Brandi M-L, Warth M, Stock J, Leisti J, Cameron D, Shepherd JJ, Öberg K, Nordenskjöld M and Salmela P (1998a) Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 83: 2621–2626
Teh BT, Esapa CT, Houlston R, Grandell U, Farnebo F, Nordenskjöld M, Pearce CJ, Carmichael D, Larsson C and Harris PE (1998b) A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild type alleles in the parathyroid tumours. Am J Hum Genet 63: 1549–1554
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Bergman, L., Teh, B., Cardinal, J. et al. Identification of MEN1 gene mutations in families with MEN 1 and related disorders. Br J Cancer 83, 1009–1014 (2000). https://doi.org/10.1054/bjoc.2000.1380
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DOI: https://doi.org/10.1054/bjoc.2000.1380
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