A novel MEN1 intronic mutation associated with multiple endocrine neoplasia type 1

Objective To investigate a family with an unusual combination of multiple endocrine neoplasia (MEN1) and the McCune–Albright syndrome for MEN1 mutations and activating GNAS1 mutations at codons Arg201 and Gln227.

Methods DNA sequences analyses were performed of the MEN1 gene and codons Arg201 and Gln227 of the GNAS1 gene, using leucocyte and endocrine tissue DNA.

Results A c→g transversion at position −9 bp in intron 9 of the MEN1 gene was identified. This resulted in the generation of a BmrI restriction endonuclease site, and its presence and segregation with MEN1 in the family was demonstrated by restriction endonuclease analysis. The c→g transversion was shown to result in the generation of a novel acceptor splice site (ccag) using reverse transcriptase-polymerase chain reaction (RT-PCR) and ribonucleic acid (RNA) obtained from Epstein-Barr virus (EBV)-transformed lymphoblasts. Utilization of this splice site resulted in an abnormal messenger RNA (mRNA) transcript that contained an additional eight bases. This predicted a frameshift that would result in nine missense amino acids followed by a premature termination signal. GNAS1 mutations were not detected in the patient with McCune–Albright syndrome.

Conclusions The occurrence of MEN1 and the McCune–Albright syndrome in this family are coincidental findings and not due to a common genetic aetiology. However, our results have identified a novel MEN1 mutation that occurs in intron 9 and generates a novel acceptor splice site. Such splicing-affecting genomic variants (SpaGVs) are increasingly being recognized as a cause of human disease, and are likely to be of significance in the 10% of MEN1 patients who do not have coding region mutations.