A Collagen10a1 mutation disrupts cell polarity in a medaka model for metaphyseal chondrodysplasia type Schmid.

Heterozygous mutations in lead to metaphyseal chondrodysplasia type Schmid (MCDS), a skeletal disorder characterized by epiphyseal abnormalities. Prior analysis revealed impaired trimerization and intracellular retention of mutant collagen type X alpha 1 chains as cause for elevated endoplasmic reticulum (ER) stress. However, how ER stress translates into structural defects remained unclear. We generated a medaka () MCDS model harboring a 5 base pair deletion in , which led to a frameshift and disruption of 11 amino acids in the conserved trimerization domain. heterozygotes recapitulated key features of MCDS and revealed early cell polarity defects as cause for dysregulated matrix secretion and deformed skeletal structures. Carbamazepine, an ER stress-reducing drug, rescued this polarity impairment and alleviated skeletal defects in heterozygotes. Our data imply cell polarity dysregulation as a potential contributor to MCDS and suggest the medaka mutant as an attractive MCDS animal model for drug screening.