A truncated COL10A1 protein causes Schmid metaphyseal chondrodysplasia via protein downregulation and impairing α1 trimer formation and secretion.
Schmid-type metaphyseal chondrodysplasia (SMCD) is primarily caused by mutations in the COL10A1 gene. This study reports a novel frameshift mutation, c.1940dup (p.Asn647Lysfs*2), identified in a Chinese SMCD pedigree. The mutation did not alter messenger RNA levels but significantly reduced COL10A1 protein expression. The mutant protein lacks the C-terminal 33 amino acids, resulting in a truncated polypeptide of 648 residues with a lower molecular weight than the wild-type protein. Degradation kinetics analysis showed no evidence of accelerated turnover. Notably, even under complete inhibition of degradation pathways, mutant protein expression remained substantially lower than that of wild-type, suggesting a potential defect in translational efficiency. Furthermore, the mutation severely disrupted the assembly of the characteristic collagen X trimer and led to markedly reduced extracellular secretion, as measured by accumulated protein levels in conditioned medium. These findings demonstrate that the c.1940dup mutation contributes to SMCD pathogenesis through coordinated mechanisms involving protein truncation, reduced expression, probable translational deficiency, and defective trimer formation and secretion, thereby revealing new potential therapeutic targets.