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

  • Jeannette L. UsherEmail author
  • David B. Ascher
  • Douglas E. V. Pires
  • Anna M. Milan
  • Tom L. Blundell
  • Lakshminarayan R. Ranganath
Research Report
Part of the JIMD Reports book series (JIMD, volume 24)


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.


Alkaptonuria Homogentisic acid Novel mutation Rare genetic disorder Sequencing 



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.

Supplementary material

346908_1_En_380_MOESM1_ESM.docx (16 kb)
Supplementary Table 1. The single-nucleotide polymorphisms (SNPs) found in the NAC AKU patients
346908_1_En_380_MOESM2_ESM.docx (20 kb)
Supplementary Table 2. The exon distribution and frequency of HGD variants in the 42 NAC patients


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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jeannette L. Usher
    • 1
    Email author
  • David B. Ascher
    • 2
  • Douglas E. V. Pires
    • 2
  • Anna M. Milan
    • 1
  • Tom L. Blundell
    • 2
  • Lakshminarayan R. Ranganath
    • 1
  1. 1.Department of Clinical Biochemistry and Metabolic MedicineRoyal Liverpool and Broadgreen University Hospital TrustLiverpoolUK
  2. 2.Department of BiochemistryUniversity of CambridgeCambridgeUK

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