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. 2003 May 13;100(10):5823-7.
doi: 10.1073/pnas.1031047100. Epub 2003 May 2.

The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome

Janet M Cronshaw  1 , Michael J Matunis
Affiliations

The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome

Janet M Cronshaw et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Figures

Figure 1
Figure 1
ALADIN localizes to the cytoplasmic face of NPCs. (A and B) Colocalization of GFP-ALADIN (green) and Nup358 (red). (C and D) Colocalization of GFP-ALADIN (green) and Tpr (red).
Figure 2
Figure 2
The C-terminal domain of ALADIN is essential for NPC targeting. The localization of GFP-tagged ALADIN constructs is shown on the left of each image (green). (A) Wild-type ALADIN. (B) ALADINR478X. (C) ALADIN1–499. The localization of NPCs is shown on the right of each image (red) by immunostaining with mAb414 (recognizes Nup358, Nup214, Nup153, and Nup62).
Figure 3
Figure 3
The N-terminal domain of ALADIN is essential for NPC targeting. The localization of GFP-tagged ALADIN constructs is shown on the left of each image (green). (A) ALADIN317–546. (B) ALADIN48–546. (C) ALADIN100–546. (D) ALADIN1–149. The localization of NPCs is shown on the right of each image (red) by immunostaining with mAb414.
Figure 4
Figure 4
Mutations in the WD-repeat domain of ALADIN affect NPC targeting. The localization of GFP-tagged ALADIN constructs is shown on the left of each image (green). (A) ALADINH160R. (B) ALADINS263P. (C) ALADINV313A. (D) ALADINQ15K. The localization of NPCs is shown on the right of each image (red) by immunostaining with mAb414.
Figure 5
Figure 5
ALADIN mutant cells are morphologically normal. Shown are electron microscopy images of wild-type (A–D) and ALADIN mutant (E–H) cells showing normal nuclei (A and E) and normal NPCs in tangential section (B and F) and cross section (C, D, G, and H). (Bars: A and E, 2 μm; B and F, 500 nm; C, D, G, and H, 100 nm.)
Figure 6
Figure 6
ALADIN mutant cells are morphologically normal. Immunostaining of nuclear structures in wild-type (Left) and ALADIN mutant (Right) cells is shown. Cells were immunostained with mAb414 (A), anti-Nup358 (B), anti-Tpr (C), anti-lamin B (D), anti-importin-β (E), and anti-transportin (F).
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