Paper

Nerve pathology is prevented by linker proteins in mouse models for LAMA2-related muscular dystrophy

Ruegg, Markus A, Previtali, Stefano C, Pelczar, Pawel, Porrello, Emanuela, Lin, Shuo, Reinhard, Judith R

2022

Overview

LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-α2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by the severe muscular dystrophy but also involves other tissues. In the dyW/dyW mouse model for LAMA2 MD, amelioration of muscle function by skeletal muscle-specific expression of the two linker proteins, mini-agrin and αLNNd, is sufficient to greatly increase survival. In such survivors, the phenotype is dominated by the hindlimb paralysis. We now show that ubiquitous expression of the two linker proteins in dyW/dyW mice improves muscle function and prevents hindlimb paralysis. The same ameliorating effect of the linker proteins was seen in dy3K/dy3K mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-α2 in many, if not all tissues affected in LAMA2 MD. Competing Interest Statement JRR and MAR are co-founders and shareholders of SEAL Therapeutics AG and inventors on a patent application filed by the University of Basel related to this work.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Agrin / Animal models / Extracellular matrix / Laminin / Muscle function / Muscular dystrophy / Neuroscience / Paralysis / Patent applications / Pathology / Phenotypes / Proteins / Skeletal muscle