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JIMD Reports, Volume 24 pp 3–11Cite as

Analysis of HGD Gene Mutations in Patients with Alkaptonuria from the United Kingdom: Identification of Novel Mutations

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Part of the book series: JIMD Reports ((JIMD,volume 24))

Abstract

Alkaptonuria (AKU) is a rare autosomal recessive disorder with incidence ranging from 1:100,000 to 1:250,000. The disorder is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD), which results from defects in the HGD gene. This enzyme converts homogentisic acid to maleylacetoacetate and has a major role in the catabolism of phenylalanine and tyrosine. To elucidate the mutation spectrum of the HGD gene in patients with alkaptonuria from 42 patients attending the National Alkaptonuria Centre, 14 exons of the HGD gene and the intron–exon boundaries were analysed by PCR-based sequencing. A total of 34 sequence variants was observed, confirming the genetic heterogeneity of AKU. Of these mutations, 26 were missense substitutions and four splice site mutations. There were two deletions and one duplication giving rise to frame shifts and one substitution abolishing the translation termination codon (no stop). Nine of the mutations were previously unreported novel variants. Using computational approaches based on the 3D structure, these novel mutations are predicted to affect the activity of the protein complex through destabilisation of the individual protomer structure or through disruption of protomer–protomer interactions.

Competing interests: None declared

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Acknowledgements

DBA is supported by a CJ Martin Fellowship from the National Health and Medical Research Council (NHMRC; GNT1072476). DEVP is funded by the Brazilian agency Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). TLB receives funding from the University of Cambridge and the Wellcome Trust.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool and Broadgreen University Hospital Trust, Duncan Building, Liverpool, L7 8XP, UK

    Jeannette L. Usher, Anna M. Milan & Lakshminarayan R. Ranganath

  2. Department of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Court Road, Cambridge, CB2 1GA, UK

    David B. Ascher, Douglas E. V. Pires & Tom L. Blundell

Authors
  1. Jeannette L. Usher
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  2. David B. Ascher
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  3. Douglas E. V. Pires
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  4. Anna M. Milan
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  5. Tom L. Blundell
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  6. Lakshminarayan R. Ranganath
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Corresponding author

Correspondence to Jeannette L. Usher .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. Division of Metabolism and Children’s Research Centre, University Children’s Hospital Zuri, Zurich, Switzerland

    Matthias Baumgartner

  3. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  4. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  5. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Viktor Kožich

Compliance with Ethics Guidelines

Jeannette Usher declares that she has no conflict of interest.

Anna Milan declares that she has no conflict of interest.

Lakshminarayan Ranganath declares that he has no conflict of interest.

David Ascher declares that he has no conflict of interest.

Douglas Pires declares that he has no conflict of interest.

Tom Blundell declares that he has no conflict of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

This article does not contain studies with animal subjects performed by any of the authors.

Details of the Contributions of Individual Authors

JU performed the sequence analysis of the HGD gene mutations, the analysis of the mutations with the freely available bioinformatics programs and the initial writing of the manuscript.

DA and DP performed the computation modelling by MCSM and DUET and the interpretation of the results.

AMM and LRR assisted with data interpretation and writing of the manuscript.

TB reviewed the result interpretation.

All authors contributed to reviewing of the manuscript.

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© 2014 SSIEM and Springer-Verlag Berlin Heidelberg

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Usher, J.L., Ascher, D.B., Pires, D.E.V., Milan, A.M., Blundell, T.L., Ranganath, L.R. (2014). Analysis of HGD Gene Mutations in Patients with Alkaptonuria from the United Kingdom: Identification of Novel Mutations. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_380

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  • DOI: https://doi.org/10.1007/8904_2014_380

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-48226-1

  • Online ISBN: 978-3-662-48227-8

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