title: Decreased expression of lysyl hydroxylase 2 (LH2) in skin fibroblasts from three Ehlers-Danlos patients does not result from mutations in either the coding or proximal promoter region of the LH2 gene.
abstract: The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue disorders characterized by tissue fragility, hyperelasticity of the skin and joint hypermobility. This phenotype, accompanied by kyphoscoliosis and/or ocular fragility, is present in patients with the autosomal recessive type VI form of EDS. These patients have significantly decreased levels of lysyl hydroxylase (LH) activity, due to mutations in the LH1 gene. LH hydroxylates specific lysine residues in the collagen molecule that are precursors for the formation of cross-links which provide collagen with its tensile strength. No disorder has been directly linked to decreased expression of LH2 and LH3, two other isoforms of LH. This study describes 3 patients with mixed phenotypes of EDS, who have significantly decreased mRNAs for LH2, but normal levels of LH1 and LH3 mRNAs, in their skin fibroblasts. In contrast to the effect of LH1 deficiency in EDS VI patients, the decreased expression of LH2 does not affect LH activity, bifunctional collagen cross-links (measured after reduction as dihydroxylysinonorleucine (DHLNL) and hydroxylysinonorleucine (HLNL)), or helical lysine hydroxylation in these cell lines. Sequence analysis of full length LH2 cDNAs and 1kb of the promoter region of LH2 does not show mutations that could explain the decreased expression of LH2. These results suggest that the deficiency of LH2 in these fibroblasts may be caused by changes in other factors required for the expression of LH2.
authors.affiliation: Division of Dermatology, Duke University Medical Ctr, Durham, NC, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Walker
authors.forename: A S
authors.initials: AS
authors.lastname: Teebi
authors.forename: J C
authors.initials: JC
authors.lastname: Marini
authors.forename: A
authors.initials: A
authors.lastname: De Paepe
authors.forename: F
authors.initials: F
authors.lastname: Malfait
authors.forename: P
authors.initials: P
authors.lastname: Atsawasuwan
authors.forename: M
authors.initials: M
authors.lastname: Yamauchi
authors.forename: H N
authors.initials: HN
authors.lastname: Yeowell
mesh_terms: D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000378:metabolism; D018076:DNA, Complementary; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006900:Hydroxylation; D008239:Lysine / Q000378:metabolism; D009154:Mutation; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D012867:Skin / Q000201:enzymology
chemical_list: D018076:DNA, Complementary; D003094:Collagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D008239:Lysine