Deficiency of ferritin heavy-chain nuclear import in Triple A syndrome implies nuclear oxidative damage as the primary disease mechanism
Open accessAbstract
Triple A syndrome is a rare autosomal recessive disorder characterized by ACTH-resistant adrenal failure, alacrima, achalasia, and progressive neurological manifestations. The majority of cases are associated with mutations in the AAAS gene, which encodes a novel, 60-kDa WD-repeat nuclear pore protein, alacrima-achalasia-adrenal insufficiency neurological disorder (ALADIN) of unknown function. Our aim was to elucidate the functional role of ALADIN by determining its interacting protein partners using the bacterial two-hybrid (B2-H) technique. Nonidentical cDNA fragments were identified from both a HeLa S-3 cell and human cerebellar cDNA library that encoded the full-length ferritin heavy chain protein (FTH1). This interaction was confirmed by both co-immunoprecipitation and fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer studies. Immunoblotting showed that fibroblasts from triple A patients (with known AAAS mutations) lack nuclear FTH1, suggesting that the nuclear translocation of FTH1 is defective. Cells transfected with FTH1 and visualized by confocal microscopy had very little nuclear FTH1, but when cotransfected with AAAS, FTH1 is readily visible in the nuclei. Therefore, FTH1 nuclear translocation is enhanced when ALADIN is coexpressed in these cells. In addition to its well known iron storage role, FTH1 has been shown to protect the nucleus from oxidative damage. Apoptosis of neuronal cells induced by hydrogen peroxide was significantly reduced by transfection of AAAS or by FTH1 or maximally by both genes together. Taken together, this work offers a plausible mechanism for the progressive clinical features of triple A syndrome.
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Defective nuclear import of the heavy chain of ferritin causes oxidative damage, apparently accounting for the pleiotropic effects of ALADIN deficiency.
“Defective nuclear import of the heavy chain of ferritin causes oxidative damage, apparently accounting for the pleiotropic effects of ALADIN deficiency (633).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [633]
The Discussion (page not available) says ALADIN deficiency impairs nuclear uptake of ferritin heavy chain, making cells more susceptible to oxidative damage, and proposes this as a plausible mechanism for triple A syndrome. It does not establish that defective import itself causes oxidative damage or definitively accounts for the syndrome’s varied effects. (LLM, conf=0.82)
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- Authors
- Storr, H. L., Kind, B., Parfitt, D. A., Chapple, J. P., Lorenz, M., Koehler, K., Huebner, A., & Clark, A. J. L.
- Affiliations
- Queen Mary University of London (GB)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Corresponding author
- Clark, Adrian J. L.
- ORCID
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2009-12
- Volume
- 23
- Issue
- 12
- Pages
- 2086-2094
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC5419132
- OpenAlex
- W2094834269
- Cited by
- 84
- References
- 40
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 7 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 4 · 2012: 6
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (GR072616MA)
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- triple A syndrome, American Association for the Advancement of Science, ALADIN, FTH1, nuclear import, nuclear translocation, nucleoporins, WD-repeat proteins, protein-protein interaction, oxidative stress, apoptosis, hydrogen peroxide, neurons, iron storage, alacrima, achalasia, adrenal insufficiency
- MeSH terms
- Adrenal Insufficiency, Apoferritins, Cell Line, Cells, Cultured, Esophageal Achalasia, Genetic Vectors, Humans, Nerve Tissue Proteins, Protein Binding, Microscopy, Confocal, Two-Hybrid System Techniques, Active Transport, Cell Nucleus, Nuclear Pore Complex Proteins, Fluorescence Resonance Energy Transfer
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