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Journal of Inherited Metabolic Disease

, Volume 36, Issue 6, pp 961–966 | Cite as

Mutations in the AGXT2L2 gene cause phosphohydroxylysinuria

  • Maria Veiga-da-Cunha
  • Nanda M. Verhoeven-Duif
  • Tom J. de Koning
  • Marinus Duran
  • Bert Dorland
  • Emile Van Schaftingen
Original Article

Abstract

Phosphohydroxylysinuria has been described in two patients with neurological symptoms, but the deficient enzyme or mutated gene has never been identified. In the present work, we tested the hypothesis that this condition is due to mutations in the AGXT2L2 gene, recently shown to encode phosphohydroxylysine phospholyase. DNA analysis from a third patient, without neurological symptoms, but with an extreme hyperlaxicity of the joints, shows the existence of two mutations, p. Gly240Arg and p.Glu437Val, both in the heterozygous state. Sequencing of cDNA clones derived from fibroblasts mRNA indicated that the two mutations were allelic. Both mutations replace conserved residues. The mutated proteins were produced as recombinant proteins in Escherichia coli and HEK293T cells and shown to be very largely insoluble, whereas the wild-type one was produced as a soluble and active protein. We conclude that phosphohydroxylysinuria is due to mutations in the AGXT2L2 gene and the resulting lack of activity of phosphohydroxylysine phospholyase in vivo. The finding that the nul alleles of p.Gly240Arg and p.Glu437Val are present at low frequencies in the European and/or North American population suggests that this condition is more common than previously thought. The diversity of the clinical symptoms described in three patients with phosphohydroxylysinuria indicates that this is most likely not a neurometabolic disease.

Keywords

HEK293T Cell Wild Type Protein North American Population Bacterial Extract Severe Growth Retardation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by grants from the Fonds National de la Recherche Scientifique (FNRS) and Fonds de la Recherche Scientifique Médicale (FRSM), the Center of Excellence des Désordres Inflammatoires dans les Affections Neurologiques (DIANE) programme of the Région Wallonne and from the ASCO industries. Maria Veiga-da-Cunha is Chercheur Qualifié of the Belgian Fonds National de la Recherche Scientifique.

Conflict of interest

None.

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Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Maria Veiga-da-Cunha
    • 1
  • Nanda M. Verhoeven-Duif
    • 2
  • Tom J. de Koning
    • 2
  • Marinus Duran
    • 3
  • Bert Dorland
    • 3
  • Emile Van Schaftingen
    • 1
  1. 1.Laboratory of Physiological Chemistry, de Duve Institute and Université Catholique de LouvainBrusselsBelgium
  2. 2.Department of Metabolic and Endocrine Diseases, Wilhelmina Children’s Hospital UtrechtUniversity Medical CenterUtrechtThe Netherlands
  3. 3.Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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