Increased intracellular proteolysis reduces disease severity in an ER stress–associated dwarfism

Lorna Mullan, Ewa Mularczyk, Louise Kung, Mitra Forouhan, Jordan Wragg, Royston Goodacre, John F. Bateman, Eileithyia Swanton, Michael Briggs, Raymond Boot-Handford

Research output: Contribution to journalArticlepeer-review


The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress–associated dwarfism MCDS.
Original languageEnglish
Pages (from-to)3861-3865
JournalThe Journal of clinical investigation
Issue number10
Early online date18 Sept 2017
Publication statusPublished - 18 Sept 2017


Dive into the research topics of 'Increased intracellular proteolysis reduces disease severity in an ER stress–associated dwarfism'. Together they form a unique fingerprint.

Cite this