Abstract
Congenital muscular dystrophy with laminin α2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin α2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin α2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3K/dy3K mice. Here, we explore the use of bortezomib in dy2J/dy2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin α2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin α2 chain.
Highlights
Mutations in the LAMA2 gene, encoding the laminin α2 chain of the extracellular matrix protein laminin-211, leads to congenital muscular dystrophy type 1A (MDC1A), which is a life threatening disease
Genotype-phenotype analyses have demonstrated that complete deficiency of laminin α2 chain causes a more severe phenotype whereas partial absence leads to a milder disease course
We found that bortezomib did not ameliorate any of the muscular dystrophy features in the dy2J/dy2J mouse model
Summary
Mutations in the LAMA2 gene, encoding the laminin α2 chain of the extracellular matrix protein laminin-211, leads to congenital muscular dystrophy type 1A (MDC1A), which is a life threatening disease. In our previously published study, we demonstrated that dy3K/dy3K mice injected twice with bortezomib had higher body weight, were more active in an exploratory locomotion test, survived longer and displayed improved muscle morphology compared to non-treated dy3K/dy3K mice [10]. The dy2J/dy2J quadriceps muscle displayed an increased number of small muscle fibers compared with wild-type muscle (S1 Fig).
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