Ehlers-Danlos syndrome type VI results from a nonsense mutation and a splice site-mediated exon-skipping mutation in the lysyl hydroxylase gene.

We have characterized a patient with Ehlers-Danlos syndrome type VI as a compound heterozygote for the lysyl hydroxylase (LH) gene, with a pathogenetic mutation in each allele contributing to the very low levels of mRNA and LH activity in his fibroblasts. Amplification of full-length LH cDNAs resulted in normal-sized (2.9-kb) and shortened (2.8-kb) transcripts indicative of two populations of alleles. One allele contained a paternally inherited C1557 to G transition that coded for a premature stop codon (Y511X) and introduced an Nhe I restriction site in exon 14 of the LH gene. The mutation in the other allele was an exon 5 deletion that produced the shortened polymerase chain reaction transcript and generated a premature stop codon at the beginning of exon 7. Sequencing of genomic DNAs spanning exon 5 showed a mutation in the consensus donor splice site at the beginning of intron 5 (gt-->at) in both the proband and his mother. Via reverse transcriptase-polymerase chain reaction, the parents' fibroblasts showed a disproportionately lower level of each mutant allele compared to their normal alleles. This study suggests that the decreased transcription of the LH gene, which may be attributed to the presence of the nonsense mutations, accounts for the LH deficiency, and consequently, this patient's clinical phenotype of Ehlers-Danlos syndrome type VI.