| First Author | Reinhard JR | Year | 2017 |
| Journal | Sci Transl Med | Volume | 9 |
| Issue | 396 | PubMed ID | 28659438 |
| Mgi Jnum | J:259548 | Mgi Id | MGI:5922242 |
| Doi | 10.1126/scitranslmed.aal4649 | Citation | Reinhard JR, et al. (2017) Linker proteins restore basement membrane and correct LAMA2-related muscular dystrophy in mice. Sci Transl Med 9(396) |
| abstractText | 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-alpha2, the long arm of the heterotrimeric (alpha2, beta1, and gamma1) basement membrane protein laminin-211 (Lm-211). We establish that despite compensatory expression of laminin-alpha4, giving rise to Lm-411 (alpha4, beta1, and gamma1), 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 alphaLNNd, consists of the N-terminal part of laminin-alpha1 and the laminin-binding site of nidogen-1. The second, called mini-agrin (mag), contains binding sites for laminins and alpha-dystroglycan. Transgenic expression of mag and alphaLNNd 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. |
