Title: A mouse model for spondyloepiphyseal dysplasia congenita with secondary osteoarthritis due to a Col2a1 mutation
Authors: Esapa, Christopher T ×
Hough, Tertius A
Testori, Sarah
Head, Rosie A
Crane, Elizabeth A
Chan, Carol P S
Evans, Holly
Bassett, J H Duncan
Tylzanowski, Przemko
McNally, Eugene G
Carr, Andrew J
Boyde, Alan
Howell, Peter G T
Clark, Anne
Williams, Graham R
Brown, Matthew A
Croucher, Peter I
Nesbit, M Andrew
Brown, Steve D M
Cox, Roger D
Cheeseman, Michael T
Thakker, Rajesh V #
Issue Date: Feb-2012
Publisher: Blackwell Science, Inc.
Series Title: Journal of Bone and Mineral Research vol:27 issue:2 pages:413-428
Abstract: Progeny of mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) revealed a mouse, designated Longpockets (Lpk), with short humeri, abnormal vertebrae, and disorganized growth plates, features consistent with spondyloepiphyseal dysplasia congenita (SEDC). The Lpk phenotype was inherited as an autosomal dominant trait. Lpk/+ mice were viable and fertile and Lpk/Lpk mice died perinatally. Lpk was mapped to chromosome 15 and mutational analysis of likely candidates from the interval revealed a Col2a1 missense Ser1386Pro mutation. Transient transfection of wild-type and Ser1386Pro mutant Col2a1 c-Myc constructs in COS-7 cells and CH8 chondrocytes demonstrated abnormal processing and endoplasmic reticulum retention of the mutant protein. Histology revealed growth plate disorganization in 14-day-old Lpk/+ mice and embryonic cartilage from Lpk/+ and Lpk/Lpk mice had reduced safranin-O and type-II collagen staining in the extracellular matrix. The wild-type and Lpk/+ embryos had vertical columns of proliferating chondrocytes, whereas those in Lpk/Lpk mice were perpendicular to the direction of bone growth. Electron microscopy of cartilage from 18.5 dpc wild-type, Lpk/+, and Lpk/Lpk embryos revealed fewer and less elaborate collagen fibrils in the mutants, with enlarged vacuoles in the endoplasmic reticulum that contained amorphous inclusions. Micro-computed tomography (CT) scans of 12-week-old Lpk/+ mice revealed them to have decreased bone mineral density, and total bone volume, with erosions and osteophytes at the joints. Thus, an ENU mouse model with a Ser1386Pro mutation of the Col2a1 C-propeptide domain that results in abnormal collagen processing and phenotypic features consistent with SEDC and secondary osteoarthritis has been established.
ISSN: 0884-0431
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Embryo and Stemcells (-)
× corresponding author
# (joint) last author

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