Objective: To investigate a family with the unusual combination of Multiple Endocrine Neoplasia (MEN1) and the McCune-Albright syndrome for mutations of the MEN1 and GNAS1 genes. MEN1 is an autosomal dominant disorder characterised by parathyroid, pancreatic and pituitary tumours whereas the McCune-Albright syndrome is a sporadic disorder characterised by polyostotic fibrous dysplasia, skin pigmentation and hyperfunctioning endocrine tumours.
Methods: Ethical committee approval was obtained, and leukocyte and endocrine tissue DNA was used with MEN1 or GNAS1 gene specific primers for polymerase chain reaction (PCR) amplification and the DNA sequence of the PCR products determined.
Results: A novel mutation involving a c→g transversion and occurring at position −9 bp in intron 9 was identified. This resulted in the generation of a BmrI restriction endonuclease site, and the presence of the mutation and its segregation with MEN1 in the family was demonstrated by restriction endonuclease. The c→g transversion also resulted in the generation of a novel acceptor splice site (ccag) and RT-PCR using RNA obtained from EBV transformed lymphoblasts demonstrated that utilisation of this splice site resulted in an abnormal mRNA transcript that contained an additional 8 bp. This predicted a frameshift that would result in 9 missense amino acids followed by a premature termination signal. MEN1 or 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 intronic abnormalities are likely to be of significance in the 10% of MEN1 who do not have mutations of the coding region. Indeed such splicing-affecting genomic variants (SpaGVs) are increasingly being recognised as a cause of human disease.