Y‐Position Collagen II Mutation Disrupts Cartilage Formation and Skeletal Development in a Transgenic Mouse Model of Spondyloepiphyseal Dysplasia

Mice were generated by pronuclear injection of a type II collagen transgene harboring an Arg789Cys (R789C) mutation that has been found in patients with spondyloepiphyseal dysplasia (SED). Expression was directed to cartilage by the murine Col2a1 promoter to examine the consequences of mutations involving the Y-position of the collagen helix Gly-X-Y triplet on skeletogenesis. The transgenic mice had very short limbs, short trunk, short snout, and cleft palate; they died at birth. Their growth plates were disorganized and collagen fibrils were sparse in cartilage matrix. When the transgene was expressed in RCS cells, there was no evidence that R789C-bearing collagen chains were incorporated into stable collagen molecules. Molecular modeling of the mutation raised the possibility that it destabilizes the collagen triple helix. Together our results suggest that Y-position mutations, such as R789C, can act in a dominant negative manner to destabilize collagen molecules during assembly, reducing their availability to form fibrils, the deficiency of which profoundly disturbs the template functions of cartilage during skeletogenesis.