![]() As the sole sites of nucleocytoplasmic transport, NPCs play a role in a variety of cellular processes, including cell-cycle progression, control of gene expression, and signal transduction. NPCs are large, multiprotein complexes that span the nuclear envelope (NE), forming a selective channel between the cytoplasm and nucleus ( 13). In a proteomic analysis of mammalian nuclear pore complexes (NPCs), we identified ALADIN as a protein that biochemically fractionates with and localizes to NPCs ( 12). This indicates that other factors play an important role in the pathogenesis of triple A syndrome. Patients with the same mutation, even patients within the same family, frequently display a high degree of variability in the clinical severity and age of onset of their symptoms ( 7, 11). There is no obvious correlation between different ALADIN mutations and disease phenotype. In addition, there are four point mutations, three of which (H160R, S263P, and V313A) are within the WD-repeat domain, whereas the fourth (Q15K) is close to the N terminus. A large number of these mutations are nonsense, frameshift, or splice-site mutations that are predicted to truncate the C terminus of ALADIN, suggesting that this domain is important for the function of ALADIN. Sequencing of the ALADIN gene from several triple A patients has identified a variety of mutations scattered throughout the gene ( 3, 4, 6– 10). However, because WD-repeat proteins play a role in a diverse range of cellular processes, the specific function of ALADIN is unknown. ![]() ![]() WD-repeat domains are thought to be involved in the assembly of macromolecular complexes ( 5), suggesting that ALADIN also may act as a scaffold for multiprotein assemblies. ALADIN is conserved in higher eukaryotes although there appears to be no direct homologue in lower eukaryotes such as Saccharomyces cerevisiae (refs. The flanking N and C termini, of ≈150 and 230 residues, respectively, contain no obvious structural domains. ALADIN is a 60-kDa protein with a central ≈170-aa domain composed of four WD repeats. The gene mutated in triple A syndrome was identified recently ( 3, 4), and the protein product of this gene was named ALADIN (also called Adracalin or AAAS). These four major symptoms, although characteristic of triple A syndrome, often are highly variable in severity and age of presentation and usually are progressive. Triple A syndrome is distinguished from other adrenal insufficiencies, however, by the additional presence of achalasia of the lower esophageal sphincter leading to swallowing difficulties, alacrima (failure to produce tears), and neurological abnormalities. Often, patients present with adrenocorticotropic hormone-resistant adrenal insufficiency, giving rise to potentially fatal hypoglycemic episodes. ![]() Triple A syndrome (also called Allgrove syndrome Online Mendelian Inheritance in Man 231550) is a rare human autosomal recessive disorder ( 1, 2). Our findings provide a foundation for understanding the molecular basis of triple A syndrome and may lead to unique insights into the role of nucleocytoplasmic transport in adrenal function and neurodevelopment. We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance and/or development of certain tissues. Importantly, these findings indicate that defects in NPC function, rather than structure, give rise to triple A syndrome. Microscopic analysis of cells from a triple A patient revealed no morphological abnormalities of the nuclei, nuclear envelopes, or NPCs. A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm. Characterization of mutant ALADIN proteins from triple A patients revealed a striking effect of these mutations on NPC targeting. Here, we present evidence indicating that NPC targeting is essential for the function of ALADIN. We showed previously that ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport. Triple A syndrome arises from mutations in a WD-repeat protein of unknown function called ALADIN (also termed Adracalin or AAAS). Triple A syndrome is a human autosomal recessive disorder characterized by an unusual array of tissue-specific defects.
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