Mutational analysis in patients with nonsyndromic MEN1

Katarina Mirkovic; Bojana Beleslin-Cokic; Jovana Vignjevic; Jelena Nikolic; Jadranka Antic; Bojana Popovic; Tatjana Isailovic; Ivana Bozic; Milan Petakov; Djuro Macut; Sanja Ognjanovic; Svetozar Damjanovic

Background: Mutational screening of the MEN1 gene has been recommended for patients who fulfill clinical criteria for familial or sporadic MEN1 and those suspicious or atypical of MEN1.

Patients and methods: Eighteen apparently unrelated individuals (6 males; 12 females, age range 16–71) with clinical manifestations of MEN1 were analised. In addition, we evaluated 7 relatives. Genomic DNA from peripheral blood leucocytes was extracted using standard procedures. PCR amplification followed by bidirectional sequencing of the entire coding region and exon-intron boundaries of the MEN1 gene was used to detect mutations.

Results: In 9/18 (50%) of the index cases we identified 9 independent germline MEN1 mutations: 3 nonsense (R527X, Y77X, Y341X), 3 frameshift (c.1089delT, c.865del4, c.960delG), 2 missense (H317Y, G225V) and one splice-site mutation (IVS4-1G>A). Three mutations were not previously reported. In addition, we detected 3 benign polymorphisms: S145S, R171Q and D418D. The patient with c.865del4 mutation was presented with insulinoma and primary hyperparathyroidism. This mutation is in exon 4 of the MEN1 gene and is predicted to cause truncation of the protein after 28 amino-acids (p.Asp252AspfsX28). Frameshift - deletion c.960delG is located in exon 6 and creates stop codon after three amino-acids (p. A263GfsX3). Patient in whom we detected this mutation had pituitary tumor and primary hyperparathyroidism. Third novel mutation, G225V, is located in exon 4 of the MEN1 gene. This patient had hyperparathyroidism, carcinoid and adrenal gland tumor. Four out of seven relatives were found to be a mutation carriers. Patient with Y341X mutation is sixteen years old boy with mixed pituitary tumor and he is at high risk for developing other MEN1 manifestations.

Conclusion: Identification of an MEN1 mutation allows genetic testing for family members who are at risk for developing disease. Only mutation-carriers among family members need careful follow-up for the clinical manifestations of MEN1 syndrome.

Endocrine Abstracts

P176