Abstract
Multiple epiphyseal dysplasia (MED) is a mild osteochondrodysplasia
characterized by mild to moderate short stature and early-onset
osteoarthritis. In this study, we found a family with MED with no
linkage to known pathogenic genes. Whole-exome sequencing revealed a
missense mutation (c.1076T>G, p.Leu359Arg,
NM_001166412.2) in SPARC-related modular calcium binding 2
(SMOC2). We generated a mouse model by knocking-in the Smoc2
mutation. Mutant mice showed short-limbed dwarfism, disorganized and
hypocellular proliferative zones and expanded hypertrophic zones in
tibial growth plates. Study of the interaction between MED proteins and
SMOC2 showed that SMOC2 and its extracellular calcium-binding (EC)
domain could interact with collagen type IX α-1 (COL9A1), however,
mutant SMOC2 could not. Our data indicated that SMOC2 mutation is
responsible for the MED phenotype. The mutation in SMOC2 affected the
interaction between SMOC2 and COL9A1.