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Linker proteins restore basement membrane and correct LAMA2-related muscular dystrophy in mice

Reinhard, Judith R. and Lin, Shuo and McKee, Karen K. and Meinen, Sarina and Crosson, Stephanie C. and Sury, Maurizio and Hobbs, Samantha and Maier, Geraldine and Yurchenco, Peter D. and Rüegg, Markus A.. (2017) Linker proteins restore basement membrane and correct LAMA2-related muscular dystrophy in mice. Science Translational Medicine, 9 (396). eaal4649.

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Abstract

LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is the most frequent form of early-onset, fatal congenital muscular dystrophies. It is caused by mutations in LAMA2, the gene encoding laminin-α2, the long arm of the heterotrimeric (α2, β1, and γ1) basement membrane protein laminin-211 (Lm-211). We establish that despite compensatory expression of laminin-α4, giving rise to Lm-411 (α4, β1, and γ1), muscle basement membrane is labile in LAMA2 MD biopsies. Consistent with this deficit, recombinant Lm-411 polymerized and bound to cultured myotubes only weakly. Polymerization and cell binding of Lm-411 were enhanced by addition of two specifically designed linker proteins. One, called αLNNd, consists of the N-terminal part of laminin-α1 and the laminin-binding site of nidogen-1. The second, called mini-agrin (mag), contains binding sites for laminins and α-dystroglycan. Transgenic expression of mag and αLNNd in a mouse model for LAMA2 MD fully restored basement membrane stability, recovered muscle force and size, increased overall body weight, and extended life span more than five times to a maximum survival beyond 2 years. These findings provide a mechanistic understanding of LAMA2 MD and establish a strong basis for a potential treatment.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
e-ISSN:1946-6242
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:26 Apr 2019 11:29
Deposited On:16 Oct 2017 10:08

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