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

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-?2, the long arm of the heterotrimeric (?2, ?1, and ?1) basement membrane protein laminin-211 (Lm-211). We establish that despite compensatory expression of laminin-?4, giving rise to Lm-411 (?4, ?1, and ?1), 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 ?LNNd, consists of the N-terminal part of laminin-?1 and the laminin-binding site of nidogen-1. The second, called mini-agrin (mag), contains binding sites for laminins and ?-dystroglycan. Transgenic expression of mag and ?LNNd 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.

SUBMITTER: Reinhard JR 

PROVIDER: S-EPMC5744687 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature