A nonsense codon of exon 14 reduces lysyl hydroxylase mRNA and leads to aberrant RNA splicing in a patient with Ehlers-Danlos syndrome type VI.

Ehlers-Danlos syndrome type VI (EDSVI) is an autosomal recessively inherited connective tissue disease, characterized by kyphoscoliosis, muscular hypotonia and ocular manifestations. The cause of the syndrome is a deficiency in the activity of lysyl hydroxylase (LH), one of the enzymes involved in the post-translational modification of collagens. We describe here an unusual compound heterozygote British patient with EDSVI. Our investigations indicate that a maternally inherited nonsense mutation (Y511X) in exon 14 of the LH gene (PLOD1) results in a reduction of the mRNA level as well as a skipping of exon 14 sequences in the mRNA that produces a protein shortened by 38 amino acids. The transcription of the other allele of the LH gene is considerably reduced from the normal for reasons that are not yet known. As a consequence, the LH activity of the skin fibroblasts of the patient is markedly reduced.