Mutant WD-repeat protein in triple-A syndrome

Tullio-Pelet, Anna; Salomon, Rémi; Hadj‐Rabia, Smail; Mugnier, Claude; Laet, Marc-Henri De; Chaouachi, B.; Bakiri, F; Brottier, Philippe; Cattolico, Laurence; Penet, Clothilde; Bégeot, Martine; Naville, Danielle; Nicolino, Marc; Chaussain, Jean‐Louis; Weissenbach, Jean; Münnich, Arnold; Lyonnet, Stanislas

doi:10.1038/81642

Cited by 289 publications

(244 citation statements)

References 20 publications

Supporting

Mentioning

233

Contrasting

Unclassified

Order By: Relevance

“…Several of the mutations identified in triple A patients result in truncation of the C terminus of ALADIN, suggesting that the C-terminal domain is important for the function of ALADIN (3,4,(7)(8)(9)(10). We analyzed the subcellular localization of the shortest pathogenic C-terminal truncation of ALADIN, the nonsense mutation R478X, which lacks the C-terminal 69 aa and terminates after glycine 477.…”

Section: The C-terminal Domain Of Aladin Is Essential For Npc Targetingmentioning

confidence: 99%

“…Sequencing of the ALADIN gene from several triple A patients has identified a variety of mutations scattered throughout the gene (3,4,(6)(7)(8)(9)(10). 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.…”

mentioning

confidence: 99%

“…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). ALADIN is a 60-kDa protein with a central Ϸ170-aa domain composed of four WD repeats.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Cronshaw

Matunis

2003

Proc. Natl. Acad. Sci. U.S.A.

165

121

View full text Add to dashboard Cite

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 and͞or 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.

show abstract

Section: The C-terminal Domain Of Aladin Is Essential For Npc Targetingmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Cronshaw

Matunis

2003

Proc. Natl. Acad. Sci. U.S.A.

165

121

View full text Add to dashboard Cite

show abstract

“…1 Triple A syndrome is caused by mutations in the AAAS gene on chromosome 12q13. 2,3 AAAS is ubiquitously expressed with an enhanced expression in the pituitary gland, the gastrointestinal tract and the adrenal gland, tissues that are mostly affected in triple A syndrome.…”

Section: Introductionmentioning

confidence: 99%

Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe

et al. 2008

View full text Add to dashboard Cite

The triple A syndrome is caused by autosomal recessively inherited mutations in the AAAS gene and is characterized by achalasia, alacrima and adrenal insufficiency as well as progressive neurological impairment. We report on a 14-year-old girl with slowly progressive axonal motor neuropathy with conspicuous muscle wasting of hypothenars and calves as well as alacrima. The mutation analysis of the AAAS gene revealed a compound heterozygous mutation: a c.251G4A mutation in exon 2 that had been reported previously, and a novel c.1288C4T mutation in exon 14. At the transcriptional level, the c.251G4A transition results in an aberrant splicing and decay of this RNA strand so that the particular clinical picture results from the novel c.1288C4T, (p.Leu430Phe, L430F) mutation in a hemizygous form.With transfection experiments, we demonstrate that GFP -ALADIN L430F correctly localizes to nuclear pore complexes. Therefore, we conclude that this point mutation impairs ALADIN function at the nuclear pore.

show abstract

“…AAAS is ubiquitously expressed in all tissues tested (Tullio-Pelet et al, 2000), but the expression of ALADIN is not reported until now.…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific expression and subcellular localization of ALADIN, the absence of which causes human triple A syndrome

et al. 2009

View full text Add to dashboard Cite

Triple A syndrome is a rare genetic disorder caused by mutations in the achalasia-addisonianism-alacrima syndrome (AAAS ) gene which encodes a tryptophan aspartic acid (WD) repeat-containing protein named alacrima-achalasia-adrenal insufficiency neurologic disorder (ALADIN). Northern blot analysis shows that the 2.1 kb AAAS mRNA is expressed in various tissues with stronger expression in testis and pancreas. We show that human ALADIN is a protein with an apparent molecular weight of 60 kDa, and expressed in the adrenal gland, pituitary gland and pancreas. Furthermore, biochemical analysis using anti-ALADIN antibody supports the previous finding of the localization of ALADIN in the nuclear membrane. The mutations S544G and S544X show that alteration of S544 residue affects correct targeting of ALADIN to the nuclear membrane.

show abstract

Mutant WD-repeat protein in triple-A syndrome

Cited by 289 publications

References 20 publications

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

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

Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe

Tissue-specific expression and subcellular localization of ALADIN, the absence of which causes human triple A syndrome

Contact Info

Product

Resources

About