The triple A syndrome (MIM#231550) is a rare autosomal recessive disorder 
characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure, 
achalasia, alacrima, and a variety of neurological and dermatological features. 
The triple A syndrome is caused by mutations in the AAAS gene, which encodes a 
protein known as ALADIN (ALacrima Achalasia aDrenal Insufficiency Neurologic 
disorder). ALADIN is a new WD-repeat protein that has no significant homology to 
any previously identified WD-repeat protein. It has been shown that it 
colocalizes with nuclear pore complexes (NPCs), a finding that strongly suggests 
an involvement of ALADIN in nucleocytoplasmic transport. An investigation of 110 
families with triple A syndrome disclosed mutation hot spots including Q15K 
(exon 1), and S293P (exon 8), which occur in 17 and 21 families from different 
geographical regions, respectively. The variable phenotype of all patients 
cannot be correlated with the localization and the nature of the ALADIN 
mutations. Thus, modifying genes/factors may be involved in the progression of 
this neurodegenerative disease. The lack of AAAS mutations in eight patients and 
negative linkage to chromosome 12q13 in three families are suggestive of genetic 
heterogeneity. To examine the cellular localization of ALADIN mutants causing 
triple A syndrome, we investigated nine different ALADIN-mutants: 2 nonsense 
(W84X, Q456X), 2 frameshift (F157fsX171, G397fsX414) and 5 point mutations 
(Q15K, L25P, H160R, S263P, L381R) by transfection experiments with green 
fluorescence protein. Mutants were predominantly localized in the cytoplasm, but 
also found in the nucleus indicating that ALADIN is essential for NPC targeting. 
To investigate physiological functions of ALADIN in vivo, we generated and 
analysed Aaas-/- knockout mice by homologous recombination in embryonic stem 
cells. Surprisingly, required animals lack any gross abnormality in adrenal and 
nervous system function. Further studies have to investigate the role of ALADIN 
at NPCs and to identify interacting proteins. Functional analyses of ALADIN may 
permit further understanding of its role for adrenocortical function and 
neurodevelopment.