title: Lysyl Hydroxylase 3 Localizes to Epidermal Basement Membrane and Is Reduced in Patients with Recessive Dystrophic Epidermolysis Bullosa.
abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1 resulting in reduced or absent type VII collagen, aberrant anchoring fibril formation and subsequent dermal-epidermal fragility. Here, we identify a significant decrease in PLOD3 expression and its encoded protein, the collagen modifying enzyme lysyl hydroxylase 3 (LH3), in RDEB. We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin. We demonstrate expression is in-part regulated by endogenous type VII collagen and that, in agreement with previous studies, even small reductions in LH3 expression lead to significantly less secreted LH3 protein. Exogenous type VII collagen did not alter LH3 expression in cultured RDEB keratinocytes and we show that RDEB patients receiving bone marrow transplantation who demonstrate significant increase in type VII collagen do not show increased levels of LH3 at the basement membrane. Our data report a direct link between LH3 and endogenous type VII collagen expression concluding that reduction of LH3 at the basement membrane in patients with RDEB will likely have significant implications for disease progression and therapeutic intervention.
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Watt
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Jasbani H S
authors.initials: JH
authors.lastname: Dayal
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Sheila
authors.initials: S
authors.lastname: Wright
authors.affiliation: Stem Cell Institute and Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Riddle
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Celine
authors.initials: C
authors.lastname: Pourreyron
authors.affiliation: The Centre for Children's Burns Research, Queensland Children's Medical Research Institute, Royal Children's Hospital, The University of Queensland, Brisbane, Australia.
authors.forename: James R
authors.initials: JR
authors.lastname: McMillan
authors.affiliation: The Centre for Children's Burns Research, Queensland Children's Medical Research Institute, Royal Children's Hospital, The University of Queensland, Brisbane, Australia.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Kimble
authors.affiliation: Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Marco
authors.initials: M
authors.lastname: Prisco
authors.affiliation: Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, United Kingdom.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gartner
authors.affiliation: Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Warbrick
authors.affiliation: Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, United Kingdom.
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Leigh
authors.affiliation: St. John's Institute of Dermatology, King's College London (Guy's Campus), London, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Basic Sciences Department, Medicine School, University of Monterrey, Monterrey, Mexico.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Salas-Alanis
authors.affiliation: Stem Cell Institute and Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom; Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
mesh_terms: D001485:Basement Membrane / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D024143:Collagen Type VII / Q000032:analysis / Q000378:metabolism; D016108:Epidermolysis Bullosa Dystrophica / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000032:analysis* / Q000378:metabolism; D060066:Protein Interaction Maps; D012867:Skin / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: D024143:Collagen Type VII; C475767:PLOD3 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase