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Mutations in the AGXT2L2 gene cause phosphohydroxylysinuria

Veiga-Da-Cunha, Maria ; Verhoeven-Duif, Nanda M. ; De Koning, Tom J. LU ; Duran, Marinus ; Dorland, Bert and Van Schaftingen, Emile (2013) In Journal of Inherited Metabolic Disease 36(6). p.961-966
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... (More)

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.

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Contribution to journal
publication status
published
subject
in
Journal of Inherited Metabolic Disease
volume
36
issue
6
pages
6 pages
publisher
Springer
external identifiers
  • scopus:84888205351
  • pmid:23242558
ISSN
0141-8955
DOI
10.1007/s10545-012-9568-9
language
English
LU publication?
no
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4fb6866b-a41f-495c-ad15-11c236a4f456
date added to LUP
2020-02-26 10:11:21
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2024-01-02 06:30:20
@article{4fb6866b-a41f-495c-ad15-11c236a4f456,
  abstract     = {{<p>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.</p>}},
  author       = {{Veiga-Da-Cunha, Maria and Verhoeven-Duif, Nanda M. and De Koning, Tom J. and Duran, Marinus and Dorland, Bert and Van Schaftingen, Emile}},
  issn         = {{0141-8955}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{6}},
  pages        = {{961--966}},
  publisher    = {{Springer}},
  series       = {{Journal of Inherited Metabolic Disease}},
  title        = {{Mutations in the AGXT2L2 gene cause phosphohydroxylysinuria}},
  url          = {{http://dx.doi.org/10.1007/s10545-012-9568-9}},
  doi          = {{10.1007/s10545-012-9568-9}},
  volume       = {{36}},
  year         = {{2013}},
}