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.