In silico analysis of the effects of disease-associated mutations of β-hexosaminidase A in Tay‒Sachs disease

Mohammad Ihsan Fazal, Rafal Kacprzyk, David J. Timson

Research output: Contribution to journalArticle

Abstract

Tay‒Sachs disease (TSD), a deficiency of β-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 protein stability 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.

Original languageEnglish
Article number42
JournalJournal of Genetics
Volume99
Issue number1
DOIs
Publication statusPublished - 15 May 2020

Keywords

  • GM2 gangliosidosis
  • inherited metabolic disease
  • protein stability
  • sphingolipidosis
  • Tay‒Sachs disease
  • β-hexosaminidase A

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