Three siblings with triple A syndrome with a novel frameshift mutation in the AAAS gene and a review of 17 independent patients with the frequent p.Ser263Pro mutation.

摘要

The triple A syndrome is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and impairment of the central, peripheral, and autonomic nervous system functions. The disease is caused by mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. In the present study, we report three siblings with triple A syndrome caused by a compound heterozygous mutation consisting of a novel Val421 frameshift mutation in exon 14 and a previously described Ser236Pro (T>C transition) missense mutation in exon 8. The second mutation is one of the most frequent mutations in the AAAS gene, occurring in 17 independent patients from different countries. With haplotype analysis, we demonstrate a founder effect for at least 13 of the 17 patients. We conclude that, although very helpful in establishing the final diagnosis of triple A syndrome, DNA analysis is not useful for the prediction of the clinical expression and outcome of the disorder. Further investigations are necessary to evaluate the correlation between genotype and clinical phenotype in the triple A syndrome.