ArticleBrain research2007
Mutational analysis of aspartoacylase: implications for Canavan disease.
Article in Brain research, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 40 citations in OpenAlex.
- Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model.Journal of inherited metabolic disease · 2009Trial
- Quantification of N-acetyl-l-aspartate in dried blood spots: A simple and fast LC-MS/MS neonatal screening method for the diagnosis of Canavan disease.Molecular genetics and metabolism · 2024Article
- Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants.Nature communications · 2024Article
- Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease.Cell & bioscience · 2024Review
- UrineHuman gene therapy · 2024Article
- Mapping the degradation pathway of a disease-linked aspartoacylase variant.PLoS genetics · 2021Article
- DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan.Neuroscience insights · 2020Review
- Review
- Two patients with Canavan disease and structural modeling of a novel mutation.Metabolic brain disease · 2017Article
- Novel mutation in an Egyptian patient with infantile Canavan disease.Metabolic brain disease · 2016Article
- Structural modeling of p.V31F variant in the aspartoacylase gene.Metabolic brain disease · 2016Article
- Atypical clinical and radiological course of a patient with Canavan disease.Metabolic brain disease · 2016Article
- A Novel Mutation in Aspartoacylase Gene; Canavan Disease.Iranian journal of child neurology · 2015Article
- Making the White Matter Matters: Progress in Understanding Canavan's Disease and Therapeutic Interventions Through Eight Decades.JIMD reports · 2015Article
- Relationship between enzyme properties and disease progression in Canavan disease.Journal of inherited metabolic disease · 2013Article
- A missense mutation (p.G274R) in gene ASPA causes Canavan disease in a Pakistani family.Molecular biology reports · 2012Article
- Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in Canavan disease?Neurochemical research · 2009Article
- Mouse aminoacylase 3: a metalloenzyme activated by cobalt and nickel.Biochimica et biophysica acta · 2009Article
- Isolation, sequence identification and tissue expression profiles of 3 novel porcine genes: ASPA, NAGA, and HEXA.Journal of applied genetics · 2008Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations that result in near undetectable activity of aspartoacylase, which catalyzes the deacetylation of N-acetyl-l-aspartate, correlate with Canavan Disease, a neurodegenerative disorder usually fatal during childhood. The underlying biochemical mechanisms of how these mutations ablate activity are poorly understood. Therefore, we developed and tested a three-dimensional homology model of aspartoacylase based on zinc dependent carboxypeptidase A. Mutations of the putative zinc-binding residues (H21G, E24D/G, and H116G), the general proton donor (E178A), and mutants designed to switch the order of the zinc-binding residues (H21E/E24H and E24H/H116E) yielded wild-type aspartoacylase protein levels and undetectable ASPA activity. Mutations that affect substrate carboxyl binding (R71N) and transition state stabilization (R63N) also yielded wild-type aspartoacylase protein levels and undetectable aspartoacylase activity. Alanine substitutions of Cys124 and Cys152, residues indicated by homology modeling to be in close proximity and in the proper orientation for disulfide bonding, yielded reduced ASPA protein and activity levels. Finally, expression of several previously tested (E24G, D68A, C152W, E214X, D249V, E285A, and A305E) and untested (H21P, A57T, I143T, P183H, M195R, K213E/G274R, G274R, and F295S) Canavan Disease mutations resulted in undetectable enzyme activity, and only E285A and P183H showed wild-type aspartoacylase protein levels. These results show that aspartoacylase is a member of the caboxypeptidase A family and offer novel explanations for most loss-of-function aspartoacylase mutations associated with Canavan Disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.