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

Transgenic expression of two small linker proteins restores muscle function and prolongs life span in a mouse model of LAMA2-related muscular dystrophy. Building a better basement membrane The most common form of congenital muscular dystrophy is caused by mutations in the gene encoding one chain of laminin-211, a basement membrane component. Deleterious muscle function results from the unstable basement membrane and lack of proper connections to the muscle plasma membrane, leading to muscle degeneration. Using a transgenic mouse model of muscular dystrophy, Reinhard et al. studied whether linker proteins could be used to fortify the basement membrane, using laminin-411 as a scaffold. Transgenic mice expressing two linker proteins—a shorter form of agrin and the fusion protein αLNNd, composed of parts of laminin-α1 and nidogen-1—had stable basement membranes, improved muscle function, and prolonged life spans. These proteins could be a missing link for muscular dystrophy therapy. 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.