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HGDiscovery: an online tool providing functional and phenotypic information on novel variants of homogentisate 1,2- dioxigenase

Malancha Karmakar, Vittoria Cicaloni, Carlos H.M. Rodrigues, Ottavia Spiga, Annalisa Santucci, David B. Ascher
doi: https://doi.org/10.1101/2021.04.26.441386
Malancha Karmakar
1Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
2Structural Biology and Bioinformatics, Department of Biochemistry, University of Melbourne, Melbourne, Victoria, Australia
3Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia
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Vittoria Cicaloni
1Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
2Structural Biology and Bioinformatics, Department of Biochemistry, University of Melbourne, Melbourne, Victoria, Australia
4Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
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Carlos H.M. Rodrigues
1Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
2Structural Biology and Bioinformatics, Department of Biochemistry, University of Melbourne, Melbourne, Victoria, Australia
3Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia
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Ottavia Spiga
4Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
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Annalisa Santucci
4Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
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David B. Ascher
1Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
2Structural Biology and Bioinformatics, Department of Biochemistry, University of Melbourne, Melbourne, Victoria, Australia
4Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
5Department of Biochemistry, Bio21 Institute, University of Cambridge, Cambridge, UK
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  • For correspondence: david.ascher@unimelb.edu.au
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Abstract

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown HGA. Mutations in the HGD gene cause AKU and they are responsible for deficient levels of functional homogentisate 1,2-dioxygenase (HGD), which, in turn, leads to excess levels of HGA. Although HGA is rapidly cleared from the body by the kidneys, in the long term it starts accumulating in various tissues, especially cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to slate blue or black. Here we report a comprehensive mutation analysis of 111 pathogenic and 190 non-pathogenic HGD missense mutations using protein structural information. Using our comprehensive suite of graph-based signature methods, mCSM complemented with sequence-based tools, we studied the functional and molecular consequences of each mutation on protein stability, interaction and evolutionary conservation. The scores generated from the structure and sequence-based tools were used to train a supervised machine learning algorithm with 84% accuracy. The empirical classifier was used to generate the variant phenotype for novel HGD missense mutations. All this information is deployed as a user friendly freely available web server called HGDiscovery (http://biosig.unimelb.edu.au/hgdiscovery/).

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • http://biosig.unimelb.edu.au/hgdiscovery/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 27, 2021.
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HGDiscovery: an online tool providing functional and phenotypic information on novel variants of homogentisate 1,2- dioxigenase
Malancha Karmakar, Vittoria Cicaloni, Carlos H.M. Rodrigues, Ottavia Spiga, Annalisa Santucci, David B. Ascher
bioRxiv 2021.04.26.441386; doi: https://doi.org/10.1101/2021.04.26.441386
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HGDiscovery: an online tool providing functional and phenotypic information on novel variants of homogentisate 1,2- dioxigenase
Malancha Karmakar, Vittoria Cicaloni, Carlos H.M. Rodrigues, Ottavia Spiga, Annalisa Santucci, David B. Ascher
bioRxiv 2021.04.26.441386; doi: https://doi.org/10.1101/2021.04.26.441386

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