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

Reinhard, Judith R. and Porrello, Emanuela and Lin, Shuo and Pelczar, Pawel and Previtali, Stefano C. and Rüegg, Markus A.. (2023) Nerve pathology is prevented by linker proteins in mouse models for LAMA2-related muscular dystrophy. PNAS Nexus, 2 (4). pgad083.

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LAMA2 -related muscular dystrophy (LAMA2 MD or MDC1A) is a devastating congenital muscular dystrophy that 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 an early-onset, severe muscular dystrophy that ultimately leads to death by respiratory insufficiency. However, pathology in non-muscle tissues has been described. Prior work in the dy W / dy W mouse model for LAMA2 MD has shown that two linker proteins, mini-agrin and αLNNd, when expressed in skeletal muscle fibers, greatly increase survival from a few months up to more than 2 years. However, the restoration of skeletal muscle function accentuates the pathology in non-muscle tissue in dy W / dy W mice, first and foremost in the peripheral nerve resulting in paralysis of the hindlimbs. We now show that expression of the two linker proteins in all tissues ameliorates the muscular dystrophy and prevents the appearance of the hindlimb paralysis. Importantly, the same ameliorating effect of the linker proteins was seen in dy 3K / dy 3K 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 muscle and peripheral nerve, which are the two organs most affected in LAMA2 MD. These results are of key importance for designing appropriate expression constructs for mini-agrin and αLNNd to develop a gene therapy for LAMA2 MD patients.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A. and Reinhard, Judith
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:12 Apr 2023 05:40
Deposited On:12 Apr 2023 05:40

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