Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature

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.

Keywords: COMP; arthritis; dysplasia; genetics; mutation; osteoarthritis.

Figure 1

Pedigree, radiographic findings and COMP mutation co-segregation in the family. (a) Pedigree of the family. Asterisk represents individuals genotyped for p.Asn453Ser COMP mutation. Black color filled symbols indicate patients with idiopathic early-onset osteoarthritis, gray color filled symbols indicate patients with dysplasia, and uncolored symbols indicate unaffected individuals. The arrow indicates the index case. (b) Hip joint radiographic findings of the 3 genotyped cases. Right hip joint of the index case (III.1) at the age of 50 years shows signs of hip osteoarthritis with superior medial narrowing of the coxofemoral joint space, subchondral condensation, and pericapital osteophytic production (Kellgren and Lawrence score of 3), without signs of dysplasia. Hip joint of his brother (III.3) shows dysplasia. No dysplasia nor osteoarthritis were shown on hip joint of her sister (III.4). (c) Electropherogram obtained by Sanger sequencing of germline DNA from index case affected by early onset osteoarthritis without dysplasia (III.1), her brother affected by dysplasia (III.3), and her unaffected sister (III.4). The arrows indicate the presence of c.1358A>G mutation of COMP in the 3 cases.

Figure 2

Schematic representation of COMP gene and protein. (a) Human COMP gene is long of 9532bp, located in chromosome 19 and composed of 19 exons. It encodes a pentameric protein of 524 kDa in which the monomers are joined together by a coiled coil domain in the N terminus. Each N-terminal domain is followed by four EGF repeat domains, eight thrombospondin (TSP) type III domains, and a C-terminal globular domain. The EGF repeat and thrombospondin type III domains are able to bind calcium ions, while the C-terminal domain is involved in interactions with other proteins in the extracellular matrix (collagens, fibronectin, aggrecan). (b) Ribbon representation of X-ray structure of COMP protein: β-sheet are colored in red, α-helices in cyan and the coils/loops in pink. Ca²⁺ ions are schematized as green spheres. Left panel: Detailed view of Ca²⁺ binding site with N453.

Figure 3

Evolutionary conservation of COMP protein around the position 453 (asparagine). Multiple sequence alignment of COMP protein sequences from different species was performed by Clustal Omega program. Residue in red (N) corresponds to the asparagine located at position 453 in the human protein (NP_000086.2). Percentage corresponds to global identity compared to the human COMP protein. Asterisk represents individuals genotyped for p.Asn453Ser COMP mutation.

Figure 4

Molecular dynamics simulation. (a) Ribbon representation of the superposition of representative structures from the WT and N453S dynamics. (b) The root mean squared fluctuations calculated on backbone atoms per COMP residue for WT and N453S dynamics simulations.