Chromosomal fragility in patients with triple A syndrome

Reshmi-Skarja, Shalini; Huebner, Angela; Handschug, K.; Finegold, David N.; Clark, Adrian J. L.; Gollin, Susanne M.

doi:10.1002/ajmg.a.10846

Cited by 20 publications

(10 citation statements)

References 37 publications

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“…Cronshaw et al recently showed that nuclei, NPCs, and the nuclear envelope appear morphologically normal (21). In this respect it is noteworthy that Reshmi-Skarja et al (14) recently described chromosomal fragility with chromosomal rearrangements involving a fragile heterochromatic region (9q12) in patients with triple A syndrome. As described by Cronshaw and Matunis (21), there is only one natural ALADIN mutant (Q15K) at the N-terminus of the protein that still localizes to NPC, suggesting that this residue may be involved in an interaction with other proteins essential for ALADIN function, but not involved in NPC localization.…”

Section: Discussionmentioning

confidence: 99%

The Triple A Syndrome Is Due to Mutations in ALADIN, a Novel Member of the Nuclear Pore Complex

Huebner

Kaindl

Knobeloch³

et al. 2004

Endocrine Research

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The triple A syndrome (MIM#231550) is a rare autosomal recessive disorder characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure, achalasia, alacrima, and a variety of neurological and dermatological features. The triple A syndrome is caused by mutations in the AAAS gene, which encodes a protein known as ALADIN (ALacrima Achalasia aDrenal Insufficiency Neurologic disorder). ALADIN is a new WD-repeat protein that has no significant homology to any previously identified WD-repeat protein. It has been shown that it colocalizes with nuclear pore complexes (NPCs), a finding that strongly suggests an involvement of ALADIN in nucleocytoplasmic transport. An investigation of 110 families with triple A syndrome disclosed mutation hot spots including Q15K (exon 1), and S293P (exon 8), which occur in 17 and 21 families from different geographical regions, respectively. The variable phenotype of all patients cannot be correlated with the localization and the nature of the ALADIN mutations. Thus, modifying genes/factors may be involved in the progression of this neurodegenerative disease. The lack of AAAS mutations in eight patients and negative linkage to chromosome 12q13 in three families are suggestive of genetic heterogeneity. To examine the cellular localization of ALADIN mutants causing triple A syndrome, we investigated nine different ALADIN-mutants: 2 nonsense (W84X, Q456X), 2 frameshift (F157fsX171, G397fsX414) and 5 point mutations (Q15K, L25P, H160R, S263P, L381R) by transfection experiments with green fluorescence protein. Mutants were predominantly localized in the cytoplasm, but also found in the nucleus indicating that ALADIN is essential for NPC targeting. To investigate physiological functions of ALADIN in vivo, we generated and analysed Aaas-/- knockout mice by homologous recombination in embryonic stem cells. Surprisingly, required animals lack any gross abnormality in adrenal and nervous system function. Further studies have to investigate the role of ALADIN at NPCs and to identify interacting proteins. Functional analyses of ALADIN may permit further understanding of its role for adrenocortical function and neurodevelopment.

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Section: Discussionmentioning

confidence: 99%

The Triple A Syndrome Is Due to Mutations in ALADIN, a Novel Member of the Nuclear Pore Complex

Huebner

Kaindl

Knobeloch³

et al. 2004

Endocrine Research

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“…A wide variety of mutations scattered through the AAAS gene have been reported in patients with triple A syndrome [23,24,25,26], resulting in a loss of function in the encoded ALADIN protein. Interestingly, there is considerable clinical variability among patients with the same genetic defect [26,27].…”

Section: Discussionmentioning

confidence: 99%

Triple A Syndrome in a Patient with Genetic Growth Hormone Insensitivity: Phenotypic Effects of Two Genetic Disorders

et al. 2012

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Background: Primary growth hormone insensitivity (GHI) and triple A syndrome are rare autosomal recessive disorders. Case Report: The patient, a 12-year-old boy from consanguineous parents, was referred for short stature at the age of 7 years (height: -5.4 SD score). He had low serum insulin-like growth factor I (IGF-I) and IGF binding protein 3 and a blunted IGF-I response to recombinant human GH; molecular analysis of the GH receptor disclosed a homozygous A_-1→G_-1 at the 5′ pseudoexon 6Ψ splice site. Recombinant IGF-I therapy (mecasermin, Increlex®, twice daily) initiated at the age of 9 years resulted in an increase of height velocity (HV) from 4.0 to 9.5 cm/year. At the age of 10.5 years, he presented with asthenia, anorexia, weight loss, a decrease in HV and very low cortisol levels; adrenal insufficiency was confirmed and glucocorticoid therapy was initiated. Subsequent peripheral motor neuropathy, achalasia and alacrima raised the suspicion of triple A syndrome, which was confirmed by the presence of a homozygous R194X mutation in the AAAS gene. Conclusion: This unusual combination of diseases, to our knowledge, has not been reported to date. Although the patient responded to recombinant IGF-I therapy for GHI, we hypothesize that the treatment could have had an inhibitory effect on 11β-hydroxysteroid dehydrogenase type 1 activity, thereby reducing the availability of cortisol and precipitating adrenal insufficiency.

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“…Because Sat III transcripts are stable transcripts that remain associated with the 9q12 regions even through the G2/M transition , one can speculate that long Sat III RNAs may be involved in a similar process. Finally, it has been suggested that Sat III RNAs may have a role in stabilizing chromosomal regions that are prone to instability and rearrangements (Bartlett et al 1988;Lamszus et al 1999; reviewed in Robertson andWolffe 2000 andin Duker 2002;Reshmi-Skarja et al 2003) (Fig. 2B).…”

Section: Molecular Traps For Transcription and Splicing Factors?mentioning

confidence: 99%

Nuclear Stress Bodies

Biamonti¹,

Vourc’h²

2010

Cold Spring Harbor Perspectives in Biology

209

201

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Nuclear stress bodies (nSBs) are unique subnuclear organelles which form in response to heat shock. They are initiated through a direct interaction between heat shock transcription factor 1 (HSF1) and pericentric tandem repeats of satellite III sequences and correspond to active transcription sites for noncoding satellite III transcripts. Given their unusual features, nSBs are distinct from other known transcription sites. In stressed cells, they are thought to participate in rapid, transient, and global reprogramming of gene expression through different types of mechanisms including chromatin remodeling and trapping of transcription and splicing factors. The analysis of these atypical and intriguing structures uncovers new facets of the relationship between nuclear organization and nuclear function.

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Chromosomal fragility in patients with triple A syndrome

Cited by 20 publications

References 37 publications

The Triple A Syndrome Is Due to Mutations in ALADIN, a Novel Member of the Nuclear Pore Complex

The Triple A Syndrome Is Due to Mutations in ALADIN, a Novel Member of the Nuclear Pore Complex

Triple A Syndrome in a Patient with Genetic Growth Hormone Insensitivity: Phenotypic Effects of Two Genetic Disorders

Nuclear Stress Bodies

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