Abstract
Background: Multiple endocrine neoplasia type 1 (MEN1) caused by MEN1 mutation is widely recognized. To date, 14 novel mutations were reported in Chinese and intronic mutations are getting more attention. Aim: To explore clinical features and MEN1 mutations in two Chinese families suffering from MEN1. Methods: Nineteen individuals (10 males and 9 females) from two unrelated families with MEN1 were studied. Mutations of MEN1 were analyzed by direct sequencing of PCR products. In vitro splicing analysis was also performed with minigenes containing both wildtype and novel mutant fragments. Through the RNAstructure program, we analyzed the secondary structure of the wild type MEN1 pre-mRNA and then introduced T>G mutation at +2 donor splice site of intron 7. Results: Clinical features of 3 patients in two families were described, and 5 individuals were proven to be carriers of MEN1 mutation without apparent symptoms. A novel splicing site mutation of the intron 7 (IVS7+2 T→G) was identified in the first family. In vitro analysis also verified this mutation caused the aberrant splicing of MEN1 mRNA. With the RNAstructure program, we could figure out that the global secondary structure as well as the number of stems and loops of pre-mRNA greatly changed after this mutation. The mutation c. 1227 C>A (C409X) was identified in another family, which also caused the truncation of menin. Conclusion: We reported a novel intronic mutation and a missense mutations in two Chinese families suffering from MEN1.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Thakker RV. Endocrine tumor syndromes. In: DeGroot LJ, Jameson JL (eds). Endocrinology. Philadelphia: Elsevier Saunders. 2006, 3509–31.
Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997, 276: 404–7.
Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 1999, 96: 143–52.
Cao Y, Liu R, Jiang X, et al. Nuclear-cytoplasmic shuttling of menin regulates nuclear translocation of {beta}-catenin. Mol Cell Biol 2009, 29: 5477–87.
Balogh K, Rácz K, Patócs A, Hunyady L. Menin and its interacting proteins: elucidation of menin function. Trends Endocrinol Metab 2006, 17: 357–64.
Pannett AA, Thakker RV. Somatic mutations in MEN type 1 tumors, consistent with the Knudson “two-hit” hypothesis. J Clin Endocrinol Metab 2001, 86: 4371–4.
Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 2008, 29: 22–32.
Jiang XH, Lu JL, Cui B, et al. MEN1 mutation analysis in Chinese patients with multiple endocrine neoplasia type 1. Endocr Relat Cancer 2007, 14: 1073–9.
Jap TS, Chiu CY, Won JG, Wu YC, Chen HS. Novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1. Clin Endocrinol (Oxf) 2005, 62: 336–42.
Tso AW, Rong R, Lo CY, et al. Multiple endocrine neoplasia type 1 (MEN1) genetic and clinical analysis in the Southern Chinese. Clin Endocrinol (Oxf) 2003, 59: 129–35.
Zha BB, Liang W, Liu J, et al. Mutation analysis in a Chinese family with multiple endocrine neoplasia type 1. Chin Med J (Eng) 2010, 123: 569–73.
Xu L, Li X, Feng B, Ni Y, Wang H, Wang L. A novel mutation of the MEN1 gene in a Chinese kindred with multiple endocrine neoplasia type 1. Endocr J 2010, 57: 839–45.
Ozturk M, Chiu CY, Akdeniz N, et al. Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1. J Endocrinol Invest 2006, 29: 523–7.
Pagon RA, Bird TD, Dolan CR, Stephens K (ed). Gene reviews. Seattle (WA): University of Washington, 1993.
Pellegata NS, Quintanilla-Martinez L, Siggelkow H, et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A 2006, 103: 15558–63.
Georgitsi M, Raitila A, Karhu A, et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab 2007, 92: 3321–5.
Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of M EN type 1 and type 2. J Clin Endocrinol Metab 2001, 86: 5658–71.
Lairmore TC, Piersall LD, DeBenedetti MK, et al. Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasia type 1 (MEN1). Ann Surg 2004, 239: 637–45.
Cardinal JW, Bergman L, Hayward N, et al. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. J Med Genet 2005, 42: 69–74.
de Herder WW, Niederle B, Scoazec JY, et al; Frascati Consensus Conference; European Neuroendocrine Tumor Society. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendo-crinology 2006, 84: 183–8.
Mathews DH, Disney MD, Childs JL, Schroeder SJ, Zuker M, Turner DH. Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. Proc Natl Acad Sci U S A 2004, 101: 7287–92.
Langer P, Cupisti K, Bartsch DK, et al. Adrenal involvement in multiple endocrine neoplasia type 1. World J Surg 2002, 26: 891–6.
Waldmann J, Bartsch DK, Kann PH, Fendrich V, Rothmund M, Langer P. Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening. Langenbecks Arch Surg 2007, 392: 437–43.
Schaefer S, Shipotko M, Meyer S, et al. Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study. Eur J Endocrinol 2008, 158: 699–704.
Krawczak M, Reiss J, Cooper DN. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 1992, 90: 41–54.
Turner JJ, Leotlela PD, Pannett AA, et al. Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2002, 87: 2688–93.
Pieterman CR, Schreinemakers JM, Koppeschaar HP, et al. Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome. Clin Endocrinol (Oxf) 2009, 70: 575–81.
Author information
Authors and Affiliations
Corresponding author
Additional information
B. Han, Z.Y. Song, and J.J. Wu contributed equally to this article.
Rights and permissions
About this article
Cite this article
Han, B., Song, Z.Y., Wu, J.J. et al. A novel intronic mutation and a missense mutation of MEN1 identified in two Chinese families with multiple endocrine neoplasia type 1. J Endocrinol Invest 36, 162–167 (2013). https://doi.org/10.3275/8336
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.3275/8336