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 inherite d connective tissue disease, characterized by kyphoscoliosis, muscular hypo tonia and ocular manifestations. The cause of the syndrome is a deficiency in the activity of lysyl hydroxylase (LH), one of the enzymes involved in t he post-translational modification of collagens. We describe here an unusua l compound heterozygote British patient with EDSVI. Our investigations indi cate that a maternally inherited nonsense mutation (Y511X) in exon 14 of th e LH gene (PLOD1) results in a reduction of the mRNA level as well as a ski pping 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 co nsiderably 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 mar kedly reduced. (C) 2000 Elsevier Science B.V. All rights reserved.