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

Cronshaw, Janet M.; Matunis, Michael J.

doi:10.1073/pnas.1031047100

Cited by 165 publications

(125 citation statements)

References 22 publications

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“…Up to now, all investigated naturally occurring pathogenic AAAS mutations result in mislocalization of ALADIN away from the NPC to a predominantly cytoplasmic distribution. 6,7 Although the mutants ALADIN Q15K and ALADIN L25P were previously described as apparently remaining at the nuclear pore, 7 ALADIN L25P turned out to be a polymorphism and ALADIN Q15K was discovered to be a missense mutation only in vitro, but in vivo results in aberrant splicing causing a frameshift followed by an early stop codon (p.G14fsX58). 7 We conclude that the leucine 430 mutation does not interfere with the correct targeting of ALADIN to the NPC but may rather be critical for the interaction of ALADIN with other protein(s) of the nuclear Before the discovery of AAAS mutations as the molecular cause for the triple A syndrome, it had already been pointed out that the significant neurological problems are common in this multisystem disorder.…”

Section: Discussionmentioning

confidence: 99%

“…5 Although the precise function of ALADIN has not yet been elucidated, it was shown that the correct localization of ALADIN at the nuclear pore plays an important role for its function. 6,7 All naturally occurring pathogenic mutations investigated so far resulted in a mislocalization of the mutant ALADIN protein in the cytoplasm or in an even distribution between the nucleus and cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…Often patient presents with potentially episode of fatal hypoglycaemia. In this syndrome, there are autonomic neurological abnormalities associated with three other symptoms including alacrima, achalasia and adrenal insufficiency named as 4S syndrome (18).…”

Section: Discussionmentioning

confidence: 99%

“…Identification of ALADIN as a component of NPCs facilitated a more detailed analysis of the molecular basis of mutations causing the disease. It has been declared that characterization of an ALADIN mutant cell line indicates that the absence of functional ALADIN cannot produce morphological abnormalities in nuclei, NPCs or NEs, indicating that the defect is functional rather than structural (18).…”

Section: Discussionmentioning

confidence: 99%

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Allgrove’s Syndrome: Two Case Reports and Review of Literature

Zamanfar¹,

Shokri²,

Shadani³

et al. 2015

J Pediatr Rev

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Introduction: Allgrove's syndrome (AS) is a rare cause of adrenal insufficiency inherited in an autosomal recessive pattern. Usually the disease is manifested during the first decade of life with severe hypoglycaemia, which can lead to sudden death. Case Presentation: Here we described two cases of Allgrove's syndrome; the first case was an 8-year-old male admitted to hospital for evaluation of seizure and gait abnormality and the second case was a 4-year-old boy admitted for evaluation of hyperpigmentation of his skin and buccal mucosa for eight months, also we made a review of literature. Conclusions: Alacrima is considered to be the earliest clinical manifestation of Triple A syndrome and early recognition of glucocorticoid deficiency would prevent hypoglycaemic convulsions, neurological sequelae and death. A carful replacement of glucocorticoids is critical to avoid adrenal crisis and allow normal growth and development.

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The Nuclear Pore Complex and Nuclear Transport

Zagairy

Fichtman

Harel

2015

Encyclopedia of Life Sciences

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The nuclear pore complex (NPC) is an essential gateway between the cell nucleus and the cytoplasm. The NPC is formed by multiple copies of ∼30 different proteins called nucleoporins, which can be divided into scaffold, membrane‐anchored and barrier components. Thousands of phenylalanine‐glycine (FG) repeats, found in barrier nucleoporins, interact to form the selective permeability barrier of the NPC channel. Shuttling nuclear transport receptors are able to interact with these FG repeats and mediate the passage of large macromolecular cargoes through the barrier. Combinations of shuttling receptors, their adaptors and localisation signals in cargo molecules define a wide array of nuclear import and export pathways. Recent research has pointed to some dynamic features in NPC components, as well as a number of nucleoporin‐related human diseases which are characterised by highly cell‐type‐specific phenotypes. Key Concepts The nuclear pore complex (NPC) is a massive and elaborate structure formed by multiple copies of ∼30 different nucleoporins. The selective permeability barrier of the NPC is formed by hydrophobic interactions among FG repeats found in a large group of nucleoporins. Ions and small molecules are able to passively diffuse through the aqueous central channel of the NPC. Macromolecules transported through the NPC must contain specific targeting signals for nuclear import and nuclear export. Targeting signals are recognised by shuttling transport receptors which mediate the passage through the NPC channel by interacting with FG repeats. A small number of inherited diseases have been linked to mutations in human nucleoporins and are characterised by cell‐type‐specific phenotypes.

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

Cited by 165 publications

References 22 publications

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

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

Allgrove’s Syndrome: Two Case Reports and Review of Literature

The Nuclear Pore Complex and Nuclear Transport

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