title: Duplication of seven exons in the lysyl hydroxylase gene is associated with longer forms of a repetitive sequence within the gene and is a common cause for the type VI variant of Ehlers-Danlos syndrome.
abstract: The type VI variant of the Ehlers-Danlos syndrome (EDS) is a recessively inherited connective tissue disorder which, in most families, is due to a deficiency in lysyl hydroxylase activity. We have recently characterized a homozygous duplication of 8.9 kb in the lysyl hydroxylase gene (PLOD) in two EDS VI families. The duplication is caused by a homologous recombination of Alu sequences in introns 9 and 16. Using PCR, we have analyzed 26 additional EDS VI families from various countries and found that 7 of them have this duplication. Our data has shown a frequency of 19.1% for this mutant allele among 35 EDS VI families studied by us so far. Our haplotype analysis shows a variation in the sequence of DNA region surrounding the duplication. There is an association between a particular allele size class, the long form, at the dinucleotide repeat within intron 16 and the duplication mutation in PLOD. Screening of a general population revealed one positive finding among 582 alleles tested. An abnormal sequence in exon 17 of the gene, which generated a stop codon in the exon sequence and aberrant mRNA processing, was responsible for the nonfunctionality of the other allele in one of the compound heterozygous patients.
authors.affiliation: Biocenter and Department of Biochemistry, University of Oulu, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Heikkinen
authors.forename: T
authors.initials: T
authors.lastname: Toppinen
authors.forename: H
authors.initials: H
authors.lastname: Yeowell
authors.forename: T
authors.initials: T
authors.lastname: Krieg
authors.forename: B
authors.initials: B
authors.lastname: Steinmann
authors.forename: K I
authors.initials: KI
authors.lastname: Kivirikko
authors.forename: R
authors.initials: R
authors.lastname: Myllylä
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D004247:DNA; D018900:Dinucleotide Repeats; D004535:Ehlers-Danlos Syndrome / Q000145:classification / Q000201:enzymology / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D016133:Polymerase Chain Reaction; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics*
chemical_list: D004247:DNA; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase