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Metabolic Brain Disease

, Volume 31, Issue 3, pp 723–726 | Cite as

Structural modeling of p.V31F variant in the aspartoacylase gene

  • Navaneethakrishnan Krishnamoorthy
  • Hatem Zayed
Short Communication

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.

Keywords

Canavan disease Aspartoacylase Genotype-phenotype correlation Mutational modeling Molecular dynamics simulation Structure-function relationship 

Notes

Acknowledgments

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.

Compliance with ethical standards

Conflict of interest

All author declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Navaneethakrishnan Krishnamoorthy
    • 1
    • 2
  • Hatem Zayed
    • 3
  1. 1.Cardiovascular Research Division, Sidra Medical and Research CentreQatar FoundationDohaQatar
  2. 2.Heart Science Centre, National Heart and Lung Institute, Imperial College LondonHarefieldUK
  3. 3.College of Health Sciences, Biomedical ProgramQatar UniversityDohaQatar

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