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      https://www.ias.ac.in/article/fulltext/jgen/099/0042

    • Keywords

       

      GM2 gangliosidosis; sphingolipidosis; inherited metabolic disease; b-hexosaminidase A; protein stability; Tay-Sachs disease

    • Abstract

       

      Tay–Sachs disease (TSD), a deficiency of b-hexosaminidase A (Hex A), is a rare but debilitating hereditary metabolic disorder. Symptoms include extensive neurodegeneration and often result in death in infancy. We report an in silico study of 42 Hex A variants associated with the disease. Variants were separated into three groups according to the age of onset: infantile (n=28), juvenile (n=9) and adult (n=5). Protein stability, aggregation potential and the degree of conservation of residues were predicted using a range of in silico tools. We explored the relationship between these properties and the age of onset of TSD. There was no significant relationship between proteinstability and disease severity or between protein aggregation and disease severity. Infantile TSD had a significantly higher mean conservation score than nondisease associated variants. This was not seen in either juvenile or adult TSD. This study has established that the degree of residue conservation may be predictive of infantile TSD. It is possible that these more highly conserved residues are involved in trafficking of the protein to the lysosome. In addition, we developed and validated software tools to automate the process of in silico analysis of proteins involved in inherited metabolic diseases. Further work is required to identify the function of well-conserved residues to establish an in silico predictive model of TSD severity.

    • Author Affiliations

       

      MOHAMMAD IHSAN FAZAL1 RAFAL KACPRZYK2 DAVID J. TIMSON3

      1. Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9PX, UK
      2. School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
      3. School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton BN2 4GJ, UK
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  • Journal of Genetics | News

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