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

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.