In silico prediction of the effects of mutations in the human triose phosphate isomerase gene: towards a predictive framework for TPI deficiency

Conor Oliver, David Timson

Research output: Contribution to journalArticle

Abstract

Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolicdisease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well- conserved residues. We predict that individuals homozygous for the corresponding mutationswould be likely to suffer from TPI deficiency.
Original languageEnglish
Pages (from-to)289-298
Number of pages10
JournalEuropean Journal of Medical Genetics
Volume60
Issue number6
DOIs
Publication statusPublished - 21 Mar 2017

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Triose-Phosphate Isomerase
Computer Simulation
Mutation
Genes
Amino Acids
Protein Stability
Catalytic Domain
Proteins

Bibliographical note

© 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/

Keywords

  • TPI deficiency
  • In silico prediction
  • Inherited metabolic disease
  • Protein stability
  • Disease-associated variant
  • Glycolytic enzyme

Cite this

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title = "In silico prediction of the effects of mutations in the human triose phosphate isomerase gene: towards a predictive framework for TPI deficiency",
abstract = "Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolicdisease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well- conserved residues. We predict that individuals homozygous for the corresponding mutationswould be likely to suffer from TPI deficiency.",
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AU - Timson, David

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N2 - Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolicdisease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well- conserved residues. We predict that individuals homozygous for the corresponding mutationswould be likely to suffer from TPI deficiency.

AB - Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolicdisease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well- conserved residues. We predict that individuals homozygous for the corresponding mutationswould be likely to suffer from TPI deficiency.

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