Relationship between enzyme properties and disease progression in Canavan disease

@article{Zano2012RelationshipBE,
  title={Relationship between enzyme properties and disease progression in Canavan disease},
  author={Stephen P. Zano and Y. S. Wijayasinghe and R. Malik and Joshua Smith and R. Viola},
  journal={Journal of Inherited Metabolic Disease},
  year={2012},
  volume={36},
  pages={1-6}
}
Canavan disease (CD) is a fatal neurological disorder caused by defects in the gene that encodes for a critical metabolic enzyme. The enzyme aspartoacylase catalyzes the deacetylation of N-acetylaspartate to produce acetate required for fatty acid biosynthesis in the brain. The loss of aspartoacylase activity leads to the demyelination and disrupted brain development that is found in CD patients. Sixteen different clinical mutants of aspartoacylase have been cloned, expressed and purified to… Expand
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
It is suggested that Hsp110 is a potential therapeutic target for misfolding ASPA variants that trigger Canavan disease due to excessive degradation as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. Expand
New T530C mutation in the aspartoacylase gene caused Canavan disease with no correlation between severity and N-acetylaspartate excretion.
TLDR
In these two sibs, urinary concentration of NAA appears to correlate inversely to symptom severity and CD progression, and a novel missense mutation causing a CD phenotype with severe clinical characteristics is found. Expand
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TLDR
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Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease
TLDR
Results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination and hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive N AA related signaling processes in oligodendrocytes. Expand
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References

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TLDR
Human aspartoacylase has now been successfully expressed in Pichia pastoris and this enzyme form has the same substrate specificity but is 150-fold more active than the E. coli-expressed enzyme. Expand
Canavan disease: Biochemical and molecular studies
TLDR
Bovine and human aspartoacylase have been purified in the laboratory and bovines and human cDNA and genomic clones have been isolated and six exons have been localized for the study of Canavan disease at the molecular level. Expand
Mutational analysis of aspartoacylase: Implications for Canavan Disease
TLDR
A three-dimensional homology model of aspartoacylase based on zinc dependent carboxypeptidase A shows that it is a member of the caboxypeptIDase A family and offers novel explanations for most loss-of-function asparticlase mutations associated with Canavan Disease. Expand
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TLDR
The clinically relevant E285A mutant reveals an altered enzyme with poor stability and barely detectable activity, while a more conservative E285D substitution leads to only fivefold lower activity than native aspartoacylase. Expand
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TLDR
The finding of a defect in the metabolism of N-acetylaspartic acid causing progressive spongy degeneration of the brain may lead to a better understanding of the function of this amino acid derivative. Expand
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TLDR
The highly ordered binding of this inhibitor has allowed assignments to be made for substrate binding groups and provides strong support for a carboxypeptidase-type mechanism for the hydrolysis of the amide bond of the substrate, N-acetyl- l-aspartate. Expand
Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.
TLDR
The specificity of cross-species hybridization of coding sequences suggests that aspartoacylase has been conserved during evolution and should now be possible to identify mutations in the noncoding genomic sequences that lead to Canavan disease and to study the regulation of ASPA. Expand
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TLDR
Predominant occurrence of certain mutations among Ashkenazi Jewish and non-Jewish patients with Canavan disease would suggest a founding-father effect in propagation of these mutant chromosomes. Expand
The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients
TLDR
The sequence of the coding region was determined in 15 non-Jewish patients and 9 new mutations were identified and the common pan-European mutation, A305E, was identified in 40% of the alleles and the overall detection rate was 93%. Expand
Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease.
TLDR
Demonstration of the same variant in two unusually mildly affected Canavan disease patients and absence of this variant in 154 control chromosomes suggest a possible pathogenic role in mild canavan disease. Expand
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