title: Generalized connective tissue disease in Crtap-/- mouse.
abstract: Mutations in CRTAP (coding for cartilage-associated protein), LEPRE1 (coding for prolyl 3-hydroxylase 1 [P3H1]) or PPIB (coding for Cyclophilin B [CYPB]) cause recessive forms of osteogenesis imperfecta and loss or decrease of type I collagen prolyl 3-hydroxylation. A comprehensive analysis of the phenotype of the Crtap-/- mice revealed multiple abnormalities of connective tissue, including in the lungs, kidneys, and skin, consistent with systemic dysregulation of collagen homeostasis within the extracellular matrix. Both Crtap-/- lung and kidney glomeruli showed increased cellular proliferation. Histologically, the lungs showed increased alveolar spacing, while the kidneys showed evidence of segmental glomerulosclerosis, with abnormal collagen deposition. The Crtap-/- skin had decreased mechanical integrity. In addition to the expected loss of proline 986 3-hydroxylation in alpha1(I) and alpha1(II) chains, there was also loss of 3Hyp at proline 986 in alpha2(V) chains. In contrast, at two of the known 3Hyp sites in alpha1(IV) chains from Crtap-/- kidneys there were normal levels of 3-hydroxylation. On a cellular level, loss of CRTAP in human OI fibroblasts led to a secondary loss of P3H1, and vice versa. These data suggest that both CRTAP and P3H1 are required to maintain a stable complex that 3-hydroxylates canonical proline sites within clade A (types I, II, and V) collagen chains. Loss of this activity leads to a multi-systemic connective tissue disease that affects bone, cartilage, lung, kidney, and skin.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Dustin
authors.initials: D
authors.lastname: Baldridge
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lennington
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Weis
authors.forename: Erica P
authors.initials: EP
authors.lastname: Homan
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.forename: Elda
authors.initials: E
authors.lastname: Munivez
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.forename: William R
authors.initials: WR
authors.lastname: Hogue
authors.forename: Shawna
authors.initials: S
authors.lastname: Pyott
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: David R
authors.initials: DR
authors.lastname: Eyre
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.forename: Roy
authors.initials: R
authors.lastname: Morello
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003238:Connective Tissue / Q000473:pathology / Q000648:ultrastructure; D003240:Connective Tissue Diseases / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D006900:Hydroxylation; D007668:Kidney / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics; D011392:Proline / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D053719:Tandem Mass Spectrometry
chemical_list: C486354:Crtap protein, mouse; D016326:Extracellular Matrix Proteins; D018832:Molecular Chaperones; D011506:Proteins; D003094:Collagen; D011392:Proline