2024-04-01
A Collagen10a1 mutation disrupts cell polarity in a medaka model for metaphyseal chondrodysplasia type Schmid
Publication
Publication
iScience , Volume 27 - Issue 109405
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. col10a1D633a 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 col10a1D633a heterozygotes. Our data imply cell polarity dysregulation as a potential contributor to MCDS and suggest the col10a1D633a medaka mutant as an attractive MCDS animal model for drug screening.
Additional Metadata | |
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Elsevier BV | |
doi.org/10.1016/j.isci.2024.109405 | |
iScience | |
Released under the CC-BY 4.0 ("Attribution 4.0 International") License | |
Organisation | Staff publications |
Tan, Wen Hui, Rücklin, M., Larionova, Daria, Ngoc, Tran Bich, van Heuven, B.-J., Marone, Federica, … Winkler, Christoph. (2024). A Collagen10a1 mutation disrupts cell polarity in a medaka model for metaphyseal chondrodysplasia type Schmid. iScience, 27(109405). doi:10.1016/j.isci.2024.109405 |