The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome.
Triple A syndrome is a human autosomal recessive disorder characterized by an unusual array of tissue-specific defects. Triple A syndrome arises from mutations in a WD-repeat protein of unknown function called ALADIN (also termed Adracalin or AAAS). We showed previously that ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport. Here, we present evidence indicating that NPC targeting is essential for the function of ALADIN. Characterization of mutant ALADIN proteins from triple A patients revealed a striking effect of these mutations on NPC targeting. A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm. Microscopic analysis of cells from a triple A patient revealed no morphological abnormalities of the nuclei, nuclear envelopes, or NPCs. Importantly, these findings indicate that defects in NPC function, rather than structure, give rise to triple A syndrome. We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues. 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.
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Janet M
JM
Cronshaw
Michael J
MJ
Matunis
D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000309:Adrenal Insufficiency / Q000235:genetics*; D002460:Cell Line; D004931:Esophageal Achalasia / Q000235:genetics*; D005808:Genes, Recessive; D006367:HeLa Cells; D006801:Humans; D007003:Hypoglycemia / Q000453:epidemiology; D007766:Lacrimal Apparatus Diseases / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins; D022022:Nuclear Pore / Q000502:physiology*; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins / Q000235:genetics*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013577:Syndrome; D014162:Transfection
C416506:AAAS protein, human; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins