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

Heterozygous mutations in COL10A1 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 ( Oryzias latipes ) MCDS model harboring a 5 base pair deletion in col10a1 , which led to a frameshift and disruption of 11 amino acids in the conserved trimerization domain. col10a1 ^Δ633a 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 col10a1 ^Δ633a heterozygotes. Our data imply cell polarity dysregulation as a potential contributor to MCDS and suggest the col10a1 ^Δ633a medaka mutant as an attractive MCDS animal model for drug screening.
Competing Interests: The authors declare no competing interests.
(© 2024 The Author(s).)