A Collagen10a1 mutation disrupts cell polarity in a medaka model for metaphyseal chondrodysplasia type Schmid
Wen Hui Tan,
Martin Rücklin,
Daria Larionova,
Tran Bich Ngoc,
Bertie Joan van Heuven,
Federica Marone,
Paul Matsudaira,
Christoph Winkler
Affiliations
Wen Hui Tan
Department of Biological Sciences and Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore
Martin Rücklin
Naturalis Biodiversity Center, Postbus 9517, 2300 RA Leiden, the Netherlands
Daria Larionova
Department of Biology, Research Group Evolutionary Developmental Biology, Ghent University, Ghent, Belgium
Tran Bich Ngoc
Department of Biological Sciences and Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore
Bertie Joan van Heuven
Naturalis Biodiversity Center, Postbus 9517, 2300 RA Leiden, the Netherlands
Federica Marone
Swiss Light Source, Paul Scherrer Institut, CH-5232 Villigen, Switzerland
Paul Matsudaira
Department of Biological Sciences and Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore
Christoph Winkler
Department of Biological Sciences and Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore; Corresponding author
Summary: 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. col10a1Δ633a 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 col10a1Δ633a heterozygotes. Our data imply cell polarity dysregulation as a potential contributor to MCDS and suggest the col10a1Δ633a medaka mutant as an attractive MCDS animal model for drug screening.
