Linker proteins restore basement membrane and correct <i>LAMA2</i>-related muscular dystrophy in mice.

Abstract

<i>L</i><i>AMA2</i>-related muscular dystrophy (<i>LAMA2</i> MD or MDC1A) is the most frequent form of early-onset, fatal congenital muscular dystrophies. It is caused by mutations in <i>LAMA2</i>, 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 <i>LAMA2</i> 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 <i>LAMA2</i> 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 <i>LAMA2</i> MD and establish a strong basis for a potential treatment.