title: Mutations in the AGXT2L2 gene cause phosphohydroxylysinuria.
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.
authors.affiliation: Laboratory of Physiological Chemistry, de Duve Institute and Université Catholique de Louvain, Avenue Hippocrate 75, 1200, Brussels, Belgium, maria.veiga@uclouvain.be.
authors.forename: Maria
authors.initials: M
authors.lastname: Veiga-da-Cunha
authors.forename: Nanda M
authors.initials: NM
authors.lastname: Verhoeven-Duif
authors.forename: Tom J
authors.initials: TJ
authors.lastname: de Koning
authors.forename: Marinus
authors.initials: M
authors.lastname: Duran
authors.forename: Bert
authors.initials: B
authors.lastname: Dorland
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
mesh_terms: D000410:Alanine Transaminase / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D002675:Child, Preschool; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D019761:Phosphorus-Oxygen Lyases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D017510:Protein Folding; D017385:Sequence Homology
chemical_list: D000410:Alanine Transaminase; C023919:O-phosphohydroxylysine phospho-lyase; D019761:Phosphorus-Oxygen Lyases