A novel mutation in the lysyl hydroxylase 1 gene causes decreased lysyl hydroxylase activity in an Ehlers-Danlos VIA patient

The clinical diagnosis of a patient with the phenotype of Ehlers-Danlos syndrome type VI was confirmed biochemically by the severely diminished level of lysyl hydroxylase (LH) activity in the patient's skin fibroblasts. A novel homozygous mutation, a single base change of T-1360-> G in exon 13 of the LH1 gene, predicted to result in W446G, was identified in the patient's full-length cDNA. This was confirmed in genomic DNA from both the patient and her parents, who were heterozygous for the mutation. This mutation was introduced into an LH1-pAcGP67 baculoviral construct and expressed, in parallel with normal LH1, in an insect cell system. The loss of LH activity in the mutated recombinant construct confirmed the pathogenicity of this mutation. Although not in the major catalytic site, this mutation occurs in a highly conserved region of the LH1 gene and may contribute to loss of activity by interfering with normal folding of the enzyme.