RT Journal Article
SR Electronic
T1 Linker proteins restore basement membrane and correct <em>LAMA2</em>-related muscular dystrophy in mice
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaal4649
DO 10.1126/scitranslmed.aal4649
VO 9
IS 396
A1 Reinhard, Judith R.
A1 Lin, Shuo
A1 McKee, Karen K.
A1 Meinen, Sarina
A1 Crosson, Stephanie C.
A1 Sury, Maurizio
A1 Hobbs, Samantha
A1 Maier, Geraldine
A1 Yurchenco, Peter D.
A1 Rüegg, Markus A.
YR 2017
UL http://stm.sciencemag.org/content/9/396/eaal4649.abstract
AB 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.