Journal
ENDOCRINE JOURNAL
Volume 59, Issue 6, Pages 523-530Publisher
JAPAN ENDOCRINE SOC
DOI: 10.1507/endocrj.EJ12-0037
Keywords
MEN1; Menin; Splicing; Minigene; Stability
Categories
Funding
- Ministry of Health, Labor and Welfare
- National Cancer Center Research and Development Fund [21-8-6, 23-A-11]
- Ministry of Health, Labour and Welfare for Research on intractable diseases [H22-Nanchi-Ippan-105]
- Foundation for Promotion of Cancer Research, Japan
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Heterozygous germline mutation of the tumor suppressor gene MEN1 is responsible for multiple endocrine neoplasia type I (MEN I), a familial cancer syndrome characterized by pituitary, parathyroid and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and its incomplete forms often manifested as familial isolated hyperparathyroidism and apparently sporadic parathyroid tumor. Mutation analysis of the MEN1 gene is a powerful tool for the early diagnosis of MEN I; however, the clinical significance of the identified mutations is not always obvious. In this study, a previously unreported missense MEN1 mutation, c.824G>T was identified in a patient with primary hyperparathyroidism and evaluated for its pathogenicity. This mutation was predicted to generate a putative missense menin protein, R275M. A stability test of the menin protein demonstrated that the stability of R275M mutant was reduced only slightly as compared with wild type menin, and therefore could not preclude the possibility that it was a rare benign polymorphism. However, further analysis of leukocyte mRNA and minigene experiments indicated that the mutant c.824G>T allele gives rise to abnormally spliced menin mRNA, and thereby confirmed that c.824G>T mutation is causative for MEN I. Thus, leukocyte mRNA analysis has been demonstrated useful to identify a splicing mutation of the MEN1 gene.
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