Structural modeling of p.V31F variant in the aspartoacylase gene
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Aspartoacylase (ASPA) is an abundant enzyme in the brain, which catalyzes the conversion of N-acetylaspartate into acetate and aspartate, deficiency in its activity leads to degeneration of the white matter of the brain and is a recognized cause of Canavan disease (CD), which affect children. Although genotype-phenotype correlation have been reported for Canavan disease patients, this relationships is still not straightforward. In this communication, we use molecular modeling to address the structural consequences resulting from the missense variant p.V31F in the ASPA enzyme, which we previously reported in a homozygous form in an Egyptian patient with infantile CD. This modeling suggests that this variant brings significant changes to the catalytic core by introducing structural flexibility through neighbouring key residues. In particular, it provides a molecular explanation for the pathogenic effect of this variant and provides a meaningful genotype-phonotype relationships. The mutational impact appears to have an influence on the function of the protein and initiates molecular event for the mechanism of the disease.
KeywordsCanavan disease Aspartoacylase Genotype-phenotype correlation Mutational modeling Molecular dynamics simulation Structure-function relationship
We would like to thank facility of research computing at Texas A&M University in Qatar for providing supercomputing. We express our gratitude to the facility of high performance computing at Imperial College London.
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Conflict of interest
All author declare that they have no conflict of interest.
- Jakobs C, ten Brink HJ, Langelaar SA, Zee T, Stellaard F, Macek M, Srsnova K, Srsen S, Kleijer WJ (1991) Stable isotope dilution analysis of N-acetylaspartic acid in CSF, blood, urine and amniotic fluid: accurate postnatal diagnosis and the potential for prenatal diagnosis of Canavan disease. J Inherit Metab Dis 14:653–660CrossRefPubMedGoogle Scholar
- Matalon R, Michals-Matalon K (1993) Canavan disease. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K (eds) GeneReviews(R). University of Washington, Seattle. All rights reserved., Seattle (WA)Google Scholar
- Zaki OK, El Abd HS, Mohamed SA, Zayed H (2015) Novel mutation in an Egyptian patient with infantile Canavan disease. Metab Brain Dis 30:1–5Google Scholar