Addison's disease and polyendocrinopathy syndromes

Project Leader(s): Dr S Pearce Addison's disease is unique amongst endocrinopathies in that if you have it, you have a 50% chance of having at least one other endocrine problem, most commonly autoimmune thyroid disease or type 1 diabetes. Thus, people with Addison's disease may be uniquely predisposed to multiple autoimmune disorders. We have been working on autoimmune polyendocrinopathy type 1 (APS1), which is also known as the APECED syndrome. People with this recessive monogenic disorder get a range of different problems but most often Addison's disease and hypoparathyroidism. We are acting as a UK reference centre for mutational analysis of this gene, and have found that UK Caucasians with APS1 almost all (>90%) have one particular mutation of the AIRE gene. This mutation is a 13 bp deletion, and appears to be at increased prevalence in the UK population (~1 in 500 healthy heterozygous carriers) due to a founder effect, more prevalent on the North West coast and possible emanating from Eire. Dr. Karen Adamson (MRC funded) is pursuing studies to find out how AIRE works in normal tissues, and has found an interesting nuclear localization for the protein, suggesting a role in transcriptional regulation.

We are also analyzing some candidate genes for Addison's disease. We have a large cohort of "non-APS1" Addison's disease subjects and are looking for association with SNP markers in a variety of candidate genes, some of which have been raised by our array experiments. We have already looked and found that the common-a-garden "non-APS1" disease is not associated with AIRE mutations, and are pursuing similar investigations. Another rare monogenic form of autoimmune disorder is termed IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), this is a devastating disorder and frequently is fatal to young boys. Dr. Kate Owen (MRC Funded) has found some mutations in a gene causing this disorder and is pursuing further detailed studies relating to its function.