title: Structural modeling of p.V31F variant in the aspartoacylase gene.
abstract: 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.
authors.affiliation: Cardiovascular Research Division, Sidra Medical and Research Centre, Qatar Foundation, Doha, Qatar.|Heart Science Centre, National Heart and Lung Institute, Imperial College London, Harefield, UK.
authors.forename: Navaneethakrishnan
authors.initials: N
authors.lastname: Krishnamoorthy
authors.affiliation: College of Health Sciences, Biomedical Program, Qatar University, Doha, Qatar. hatem.zayed@qu.edu.qa.
authors.forename: Hatem
authors.initials: H
authors.lastname: Zayed
mesh_terms: D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D017825:Canavan Disease / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008958:Models, Molecular; D009154:Mutation
chemical_list: D000581:Amidohydrolases; C019751:aspartoacylase
keywords: Aspartoacylase; Canavan disease; Genotype-phenotype correlation; Molecular dynamics simulation; Mutational modeling; Structure-function relationship