STRUCTURE AND EXPRESSION OF THE HUMAN LYSYL HYDROXYLASE GENE (PLOD) -INTRON-9 AND INTRON-16 CONTAIN ALU SEQUENCES AT THE SITES OF RECOMBINATION IN EHLERS-DANLOS-SYNDROME TYPE-VI PATIENTS

Lysyl hydroxylase (EC 1.14.11.4) catalyzes the formation of hydroxylys ine in collagens by the hydroxylation of lysine residues in peptide li nkages. This enzyme activity is known to be reduced in patients with t he type VI variant of the Ehlers-Danlos syndrome, and the first mutati ons in the lysyl hydroxylase gene (PLOD) have recently been identified . We have now isolated genomic clones for human lysyl hydroxylase and determined the complete structure of the gene, which contains 19 exons and a 5' flanking region with characteristics shared by housekeeping genes. The constitutive expression of the gene in different tissues fu rther suggests that lysyl hydroxylase has an essential function. We ha ve sequenced the introns of the gene in the region where many mutation s and rearrangements analyzed to date are concentrated. Intron 9 and i ntron 16 show extensive homology resulting from the many Alu sequences found in these introns. Intron 9 contains five and intron 16 eight Al u sequences. The high homology and many short identical or complementa ry sequences in these introns generate many potential recombination si tes with the gene. The delineation of the structure of the lysyl hydro xylase gene contributes significantly to our understanding of the rear rangements in the genome of Ehlers-Danlos type VI patients. (C) 1994 A cademic Press, Inc.