A novel splice site mutation of the <i>MEN1</i> gene identified in a patient with primary hyperparathyroidism

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a relatively rare autosomal dominantly inherited condition characterized by hyperplastic and neoplastic disorder of endocrine organs such as the parathyroid, anterior pituitary and gastroenteropancreatic endocrine tissues [1]. Primary hyperparathyroidism (PHPT) is the most common disorder, and is usually the initial manifestation in MEN1. Its prevalence in MEN1 patients during lifetime is nearly 100%, and the average age of onset is during the third decade of life, which is much earlier than that of sporadic primary hyperparathyroidism [2,3] abstract. Heterozygous germline mutation of the tumor suppressor gene MEN1 is responsible for multiple endocrine neoplasia type 1 (MEN1), 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 MEN1; 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 MEN1. Thus, leukocyte mRNA analysis has been demonstrated useful to identify a splicing mutation of the MEN1 gene.

A Novel Missense Mutation of the <i>MEN1</i> Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity

“…Tumorigenesis in the MEN1 patients is commonly explained by Knudson's two-hit theory with a loss of heterozygosity in the MEN1 gene (3,4). Therefore, DNA testing for MEN1 is an established and useful tool for the diagnosis of MEN1 (1,5,6). As previously reported, 20-30% of the germline MEN1 mutations are missense mutations (2,5).…”

Proposition of adjustments to the ACMG‐AMP framework for the interpretation of MEN1 missense variants

“…The MENIN has numerous molecular functions (DNA‐, protein‐, and chromatin‐binding) and is involved in many biological processes such as negative regulation of cell cycle, DNA repair, regulation of transcription and telomerase activity. The study of mutant MENIN protein stability seems to be more relevant than proliferation studies (Nagamura et al, ; Nozières et al, ). After parathyroidectomy or other surgery, MENIN immunostaining is exceptionally performed.…”

“…The study of mutant MENIN protein stability seems to be more relevant than proliferation studies (Nagamura et al, 2012;Nozières et al, 2014).…”

Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel <i>CDC73</i> mutation

“…Although HPT-JT is a rare tumor syndrome, it cannot be overlooked because parathyroid carcinoma develops more frequently in this syndrome than other selected for MEN1 (12 articles, 30 patients) [12][13][14][15][16] and HPT-JT (9 articles, 35 patients) [17][18][19][20]. Serum calcium levels ranged from 10.8 to 17.5 mg/dL (mean 12.3 mg/dL, median 13.2 mg/dL) at 25-35 years old in MEN1 cases, and 12.0 to 16.8 mg/dL (mean 13.7 mg/dL, median 11.5 mg/dL) in HPT-JT cases (Fig.…”