Abstract
Metachromatic leukodystrophy (MLD) is a neurodegenerative disorder characterized by progressive demyelination resulting from impaired degradation and thus the accumulation of cerebroside-3-sulfate (sulfatide). It is caused by the deficiency of arylsulfatase A (ARSA) enzyme which is encoded by the ARSA gene. The present study reports the clinical, molecular, and bioinformatic investigation of three patients belonging to a consanguineous family with late-infantile MLD disorder. The results revealed a novel homozygous missense mutation c.699C>A (p.His231Gln) in exon 4 of ARSA gene in the three patients inherited from their heterozygous parents. Interestingly, this novel mutation is the second mutation identified in the substrate-binding site of ARSA protein and it was classified as damaging and deleterious by several bioinformatics tools. The c.699C>A (p.His231Gln) leads to changes in the pre-mRNA secondary structure and in the ARSA protein 3D structure with a significant root mean square deviation value which could probably affect its stability and function.
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Acknowledgments
We thank the patients and their families for their cooperation in the present study. This work was supported by The Ministry of the Higher Education and the Scientific Research in Tunisia. We also extend our thanks to the doctors of NeuroPediatrics Service in the CHU Hedi Chaker of Sfax, for their help and availability. We owe special thanks to Mr. Wassim Hariz, founder and former head of the English Unit and Editorial Board at the Sfax Faculty of Science, for having proofread this paper.
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Highlights
- Novel homozygous mutation p.His231Gln among the substrate binding site of catalytic domain of ARSA protein was identified in three patients with metachromatic leukodystrophy.
- The bioinformatics investigations supported the pathogenicity of the novel p.His231Gln mutation and classify it as damaging and deleterious.
- The three patients belonging to a consanguineous family and shearing the same novel deleterious homozygous mutation p.His231Gln presented late-infantile form, but with clinical heterogeneity.
- To our knowledge, p.His231Gln is the second mutation identified in the substrate-binding site and it is described for the first time in patients with metachromatic leukodystrophy.
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Issa, A.B., Feki, F.K., Jdila, M.B. et al. Clinical, Molecular, and Computational Analysis Showed a Novel Homozygous Mutation Among the Substrate-Binding Site of ARSA Protein in Consanguineous Family with Late-Infantile MLD. J Mol Neurosci 66, 17–25 (2018). https://doi.org/10.1007/s12031-018-1141-z
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DOI: https://doi.org/10.1007/s12031-018-1141-z