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Generalized connective tissue disease in Crtap-/- mouse.

Authors :
Dustin Baldridge
Jennifer Lennington
MaryAnn Weis
Erica P Homan
Ming-Ming Jiang
Elda Munivez
Douglas R Keene
William R Hogue
Shawna Pyott
Peter H Byers
Deborah Krakow
Daniel H Cohn
David R Eyre
Brendan Lee
Roy Morello
Source :
PLoS ONE, Vol 5, Iss 5, p e10560 (2010)
Publication Year :
2010
Publisher :
Public Library of Science (PLoS), 2010.

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.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
5
Issue :
5
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.2455921e2124b3abb340b3b7c2df942
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0010560