Abstract
The role of genetics in the development of osteoarthritis is well established but the molecular bases are not fully understood. Here, we describe a family carrying a germline mutation in COMP (Cartilage Oligomeric Matrix Protein) associated with three distinct phenotypes. The index case was enrolled for a familial form of idiopathic early-onset osteoarthritis. By screening potential causal genes for osteoarthritis, we identified a heterozygous missense mutation of COMP (c.1358C>T, p.Asn453Ser), absent from genome databases, located on a highly conserved residue and predicted to be deleterious. Molecular dynamics simulation suggests that the mutation destabilizes the overall COMP protein structure and consequently the calcium releases from neighboring calcium binding sites. This mutation was once reported in the literature as causal for severe multiple epiphyseal dysplasia (MED). However, no sign of dysplasia was present in the index case. The mutation was also identified in one of her brothers diagnosed with MED and secondary osteoarthritis, and in her sister affected by an atypical syndrome including peripheral inflammatory arthritis of unknown cause, without osteoarthritis nor dysplasia. This article suggests that this mutation of COMP is not only causal for idiopathic early-onset osteoarthritis or severe MED, but can also be associated to a broad phenotypic variability with always joint alterations.