Sandbox MEN genetics
- The gene locus causing MEN1 has been localised to chromosome 11q13 by studies of loss of heterozigosity (LOH) on MEN1-associated tumors and by linkage analysis in MEN1 families[1][2][3][4]
- MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.
- MEN1 gene is a putative tumor suppressor gene and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for tumor development.[5]
- Knudson's "two hits" model for tumor development suggest that there is a germline mutation present in all cells at birth and the second mutation is a somatic mutation that occurs in the predisposed endocrine cell and leads to loss of the remaining wild type allele. This "two hits" model gives cells the survival advantage needed for tumor development.
- Mutations are distributed over the entire coding region without showing any significant hot spot region[6][7][8][9][10][11]
- Approximately 20% of mutations are nonsense mutations, about 50% are frameshift insertions and deletions, 20% are missense mutations and about 7% are splice site defects.
- ↑ Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M (1988). "Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma". Nature. 332 (6159): 85–7. doi:10.1038/332085a0. PMID 2894610.
- ↑ Thakker RV, Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK; et al. (1989). "Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11". N Engl J Med. 321 (4): 218–24. doi:10.1056/NEJM198907273210403. PMID 2568587.
- ↑ Friedman E, Sakaguchi K, Bale AE, Falchetti A, Streeten E, Zimering MB; et al. (1989). "Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1". N Engl J Med. 321 (4): 213–8. doi:10.1056/NEJM198907273210402. PMID 2568586.
- ↑ Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B; et al. (1990). "Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors". Proc Natl Acad Sci U S A. 87 (5): 1968–72. PMC 53606. PMID 1968641.
- ↑ Knudson AG (1993). "Antioncogenes and human cancer". Proc Natl Acad Sci U S A. 90 (23): 10914–21. PMC 47892. PMID 7902574.
- ↑ Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC; et al. (1997). "Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states". Hum Mol Genet. 6 (7): 1169–75. PMID 9215689.
- ↑ Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N; et al. (1998). "Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders". Am J Hum Genet. 63 (2): 455–67. doi:10.1086/301953. PMC 1377295. PMID 9683585.
- ↑ Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G; et al. (1998). "Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism". J Clin Endocrinol Metab. 83 (8): 2621–6. doi:10.1210/jcem.83.8.5059. PMID 9709921.
- ↑ Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ; et al. (1999). "Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases". Hum Mutat. 13 (1): 54–60. doi:10.1002/(SICI)1098-1004(1999)13:1<54::AID-HUMU6>3.0.CO;2-K. PMID 9888389.
- ↑ Hai N, Aoki N, Matsuda A, Mori T, Kosugi S (1999). "Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1)". Eur J Endocrinol. 141 (5): 475–80. PMID 10576763.
- ↑ Morelli A, Falchetti A, Martineti V, Becherini L, Mark M, Friedman E; et al. (2000). "MEN1 gene mutation analysis in Italian patients with multiple endocrine neoplasia type 1". Eur J Endocrinol. 142 (2): 131–7. PMID 10664520.