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Human lysyl hydroxylase. cDNA cloning, chromosomal assignment, regulation of gene expression and analysis of mutations in patients with type VIA Ehlers-Danlos syndrome



Human lysyl hydroxylase. cDNA cloning, chromosomal assignment, regulation of gene expression and analysis of mutations in patients with type VIA Ehlers-Danlos syndrome



Acta Universitatis Ouluensis Series A Scientiae Rerum Naturalium 0(252): 1-60



Lysyl hydroxylase (EC 1.14.11.4), an alpha-2 dimer, catalyzes the formation of hydroxylysine residues in collagens and related proteins. These hydroxylysine residues serve as attachment sites for carbohydrates and create intra- and intermolecular cross-links. The importance of the lysyl hydroxylase is demonstrated in patients with the type VIA Ehlers-Danlos syndrome (EDS) which is caused by reduced activity of the enzyme. In the present work, cDNA clones for lysyl hydroxylase were characterized, genetic defects responsible for the type VIA EDS were identified and effect of minoxidil, an antihypertensive drug, on the lysyl hydroxylase gene expression was examined. The cDNA for lysyl hydroxylase contains a coding region of 2181 nucleotides and 788 nucleotides of 3' untranslated sequences. The amino acid sequences derived from the cDNA show a 76% identity between human and chicken with the highest conservation at the C-terminal region. The molecular weight of the polypeptide is 81 570 calculated from the cDNA. The lysyl hydroxylase gene was localized on chromosome 1 at p36.2-36.3 using in situ hybridization on metaphase chromosomes in the laboratory of Dr. T.B. Shows, Buffalo, New York. The first patients with the type VIA EDS were genetically characterized in the present study. A homozygous partial duplication of the lysyl hydroxylase gene was found to be responsible for the disease in two unrelated families. The duplication consists of seven exons of the gene covering some of the highly conserved regions of the polypeptide thus considerably reducing the enzyme activity. The mRNA for lysyl hydroxylase in the patients was 780 nucleotides and the gene about 6 to 9 kb larger than normal. The duplication was found to be caused by unequal crossing-over between two homologous Alu-repeats in two introns of the gene. Uniparental isodisomy was excluded using highly variable dinucleotide markers for chromosome 1. PCR method for detection of the mutation was also developed. Effect of minoxidil on the gene expression of lysyl hydroxylase was studied in cultured skin fibroblasts by determination amount of mRNA. Minoxidil was found to reduce the amount of mRNA for lysyl hydroxylase while the amounts of control mRNAs were unaltered. The data presented in this study supports the specific nature of the inhibition.

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