Novel COL9A3 mutation in a family diagnosed with multiple epiphyseal dysplasia: a case report

Abstract

Background: Multiple epiphyseal dysplasia is a common skeletal dysplasia characterized by mild short stature, early-onset osteoarthritis mainly involving the hip and knee joints, and abnormally small and/or irregular epiphyses. Multiple epiphyseal dysplasia is clinically and genetically heterogeneous and six genes are associated with the phenotype of multiple epiphyseal dysplasia.

Case presentation: A 12-year-old Korean boy presented with intermittent knee pain. His height was 144.6 cm (20th percentile) and family history was notable for early-onset osteoarthritis in his father. The proband's x-rays revealed epiphyseal changes characteristic of multiple epiphyseal dysplasia associated with a collagen IX defect, with manifestations primarily restricted to the knees. Mutational analysis identified a novel c.104G>A substitution in exon 2 of COL9A3, resulting in p.Gly35Asp in the proband and his father. In silico analyses predicted the p.Gly35Asp amino acid change to be detelerious, and molecular dynamics simulation demonstrated a major structural change in the heterotrimeric collagen IX.

Conclusion: So far, three COL9A3 mutations, have been reported. These three mutations are located at the splice donor or acceptor site of COL9A3 and cause skipping of exon 3, resulting in the deletion of 12 aminoacids in the COL3 domain of COL9A3. In contrast, the novel missense mutation identified in this two-generation family with multiple epiphyseal dysplasia is a missense mutation affecting the Gly residue of the Pro-Pro-Gly repeat sequence in the COL3 domain of collage IX, with accompanying major structural change of the collagen peptide.

Figure 1

Radiographs of proband at the age of 12 years. Anteroposterior view of knee joint showed shortening, fragmentation, and joint surface irregularity of distal femoral and proximal tibial epiphysis (A, B). Anteroposterior view of distal tibial epiphysis showed a lateral wedging and fragmentation (C, D). The tarsal navicular and cuneiform bone showed irregular ossification (E). The epiphysis of distal radius was wedge shaped and the epiphyses of the distal ulnae were relatively small and the carpal bone shows dysplasia and flattening (F). The epiphyses of proximal femur were spared (G).

Figure 2

Radiographs of the proband’s father at the age of 41 years. Anteroposterior view of knee joints revealed early osteoarthritis with findings including of medial joint space narrowing and joint surface irregularity (A). The capital femoral epiphysis of the proband’s father has no evidence of dysplasia (B).

Figure 3

MD simulation of wild type and mutant model structure of trimer collagen. Wild type model structure (A), twisted form of the mutant (B), collagen-collagen interaction by a hydrogen bonding in wild type (C), the substitution of glycine to aspartic acid causing an interaction with the self strand (D), C-alpha distance between residues in wild type and mutant trimer (E and F), respectively, and energy plot of wild type and mutant collagen by Amber-GPU (G).