title: Reduction of lysyl hydroxylase 3 causes deleterious changes in the deposition and organization of extracellular matrix.
abstract: Lysyl hydroxylase 3 (LH3) is a multifunctional enzyme possessing lysyl hydroxylase, collagen galactosyltransferase, and glucosyltransferase (GGT) activities. We report here an important role for LH3 in the organization of the extracellular matrix (ECM) and cytoskeleton. Deposition of ECM was affected in heterozygous LH3 knock-out mouse embryonic fibroblasts (MEF(+/-)) and in skin fibroblasts collected from a member of a Finnish epidermolysis bullosa simplex (EBS) family known to be deficient in GGT activity. We show the GGT deficiency to be due to a transcriptional defect in one LH3 allele. The ECM abnormalities also lead to defects in the arrangement of the cytoskeleton in both cell lines. Ultrastructural abnormalities were observed in the skin of heterozygous LH3 knock-out mice indicating that even a moderate decrease in LH3 has deleterious consequences in vivo. The LH3 null allele in the EBS family member and the resulting abnormalities in the organization of the extracellular matrix, similar to those found in MEF(+/-), may explain the correlation between the severity of the phenotype and the decrease in GGT activity reported in this family.
authors.affiliation: Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Risteli
authors.affiliation: Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Ruotsalainen
authors.affiliation: Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Antti M
authors.initials: AM
authors.lastname: Salo
authors.affiliation: Department of Pathology, Biocenter Oulu, P.O. Box 5000, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Sipilä
authors.affiliation: Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Baker
authors.affiliation: Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Shireen R
authors.initials: SR
authors.lastname: Lamandé
authors.affiliation: Dermatology Clinic, Kainuu Central Hospital, 87140 Kajaani, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Vimpari-Kauppinen
authors.affiliation: Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland. Electronic address: raili.myllyla@oulu.fi.
authors.forename: Raili
authors.initials: R
authors.lastname: Myllylä
mesh_terms: D000199:Actins / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D024142:Collagen Type VI / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D016110:Epidermolysis Bullosa Simplex / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000648:ultrastructure; D014404:Tubulin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D024142:Collagen Type VI; D005353:Fibronectins; D014404:Tubulin; D014746:Vimentin; C510730:lysyl hydroxylase 3, mouse; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D005964:Glucosyltransferases
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