A study just published in PLOS one by Dongsheng Huang and Peiqiang Su from China showing that a glycine substitution (p.Gly1170Ser) in type II collagen (COL2A1) can cause mutant protein retention in the endoplasmic reticulum (ER), resulting in ER stress, induction of the unfolded protein response (UPR) and downstream consequences such as reduce chondrocyte proliferation and increased abnormal apoptosis.
These are similar disease mechanisms to PSACH-MED caused by COMP and matrilin-3 mutations and potentially point to common disease mechanisms
This particular mutation (p.Gly1170Ser) was previously shown to cause “premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calvé-Perthes disease in a single family” and is therefore an interesting mutation to model.
In this large 5-generation family sixteen affected members were identified:-
- 5 with isolated precocious hip osteoarthritis (OA)
- 6 with avascular necrosis (AVN) of the femoral head
- 5 with Legg-Calvé-Perthes disease (LCP)
All affected individuals, regardless of the phenotype, were heterozygous for p.Gly1170Ser in COL2A1.
Patient cartilage studies had previously noted that the “hierarchical structure of the mutant cartilage and the embedded chondrocytes were markedly abnormal”. Moreover, “ultrastructural examination showed obvious abnormal chondrocytes and disarrangement of collagen fibres in the mutant cartilage”.
Interestingly, we have previously reported the identification of COL2A1 mutations in two families with unclassified forms of multiple epiphyseal dysplasia (MED); both of these mutations, p.Gly1179Arg and p.Gly1176Val, are within several residues of the p.Gly1170Ser reported in this current study.
We had hypothesised that there might be similar disease mechanisms shared between the MED, AVN, LCP and precocious OA phenotypic spectrum, and this hypothesis is now supported by the recent study of the p.Gly1170Ser mouse model, which shows many features that are in common with the PSACH-MED models of Matn3 (p.V194D) and Comp (p.D469del & p.T585M).