In the present study, we have characterized a patient with Ehlers-Danlos syndrome type VI (EDS VI) as homozygous for a pathogenetic mutation in the lysyl hydroxylase 1 (LH1) gene. This mutant allele contributes to very low levels of LH1 mRNA and severely diminished LH activity in his skin fibroblasts. The reduced hydroxylysine content of collagen was reflected in the increased electrophoretic mobility of the type I collagen alpha1 and alpha2 chains precipitated from cell and media samples of cultured patient fibroblasts. The homozygous mutation, a single base change of C1557 --> G which would convert a codon for tyrosine (TAC) at residue 511 to a stop codon (TAG) in exon 14 of the LH1 gene, was identified in full-length cDNAs for LH1 amplified from the patient's fibroblasts. We have demonstrated that the low level of LH activity measured in his fibroblasts may result from a minor processing pathway in which an in-frame skipping of exon 14 containing the mutation restores partial function of the enzyme. The mutation was confirmed in both alleles in genomic DNA from the proband and by the maternal inheritance of this mutation. The father's DNA was unavailable for analysis. The autosomal recessive nature of EDS VI was verified by the fact that the mother, who has one mutated and one normal allele, is clinically unaffected by this disorder. This mutation, which has been previously observed in another unrelated compound heterozygous patient, may prove to be a more widespread mutation for EDS VI.
Copyright 1999 Academic Press.