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.