Abstract
The COL2A1 gene encodes the α1(II) chain of the homotrimeric type II collagen, the most abundant protein in cartilage. In humans, COL2A1 mutations create many clinical phenotypes collectively termed type II collagenopathies; however, the genetic basis of the phenotypic diversity is not well elucidated. Therefore, animal models corresponding to multiple type II collagenopathies are required. In this study we identified a novel Col2a1 missense mutation—c.44406A>C (p.D1469A)—produced by large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis in a mouse line. This mutation was located in the C-propeptide coding region of Col2a1 and in the positions corresponding to a human COL2A1 mutation responsible for platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T). The phenotype was inherited as a semidominant trait. The heterozygotes were mildly but significantly smaller than wild-type mice. The homozygotes exhibited lethal skeletal dysplasias, including extremely short limbs, severe spondylar dysplasia, severe pelvic hypoplasia, and brachydactyly. As expected, these skeletal defects in the homozygotes were similar to those in PLSD-T patients. The secretion of the mutant proteins into the extracellular space was disrupted, accompanied by abnormally expanded rough endoplasmic reticulum (ER) and upregulation of ER stress-related genes, such as Grp94 and Chop, in chondrocytes. These findings suggested that the accumulation of mutant type II collagen in the ER and subsequent induction of ER stress are involved, at least in part in the PLSD-T–like phenotypes of the mutants. This mutant should serve as a good model for studying PLSD-T pathogenesis and the mechanisms that create the great diversity of type II collagenopathies.
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Acknowledgments
We are grateful to Dr. S. Tominaga, Mrs. H. Yokoyama, and J. Nagano for their help with managing the animals, preparation of samples, identification of the mutation, and mouse genotyping. We also thank Charles River Laboratories Japan, Inc. for help with mouse breeding. This project was supported by grants-in-aid from the Ministry of Education, Culture, Sports and Science of Japan (contract grant Nos. 20390408 and 21249080), Research on Child Health and Development (contract grant No. 20-S-3), and Naito Foundation.
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Furuichi, T., Masuya, H., Murakami, T. et al. ENU-induced missense mutation in the C-propeptide coding region of Col2a1 creates a mouse model of platyspondylic lethal skeletal dysplasia, Torrance type. Mamm Genome 22, 318–328 (2011). https://doi.org/10.1007/s00335-011-9329-3
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DOI: https://doi.org/10.1007/s00335-011-9329-3