The laminin α2 expressed by dystrophic dy2J mice is defective in its ability to form polymers

Mutations in LAMA2 cause severe congenital muscular dystrophy accompanied by nervous system defects [1]. Mice homozygous for the dy2J allele of LAMA2 express a laminin α2 subunit that has a deletion in the aminoterminal domain VI, providing an animal model for study of the molecular basis of congenital muscular dystrophy [2,3]. Domain VI is predicted to be involved in laminin polymerization, along with amino-terminal domains from laminin β and γ chains [4]. In a solutionpolymerization assay, we found that purified dy2J laminin assembled poorly and formed little polymer, in contrast to wild-type muscle laminin. Furthermore, dissolution of the collagen IV network caused dy2J laminin to be released into solution, indicating that laminin polymers within the skeletal muscle basement membrane were defective. In addition to loss of polymerization, dy2J laminin had a reduced affinity for heparin. Finally, recombinant laminin engineered with the dy2J deletion was more sensitive to proteolysis and was readily cleaved near the junction of domains V and VI. Thus, the dy2J deletion selectively disrupts polymer formation, reduces affinity for heparin, and destabilizes domain VI. These are the first specific functional defects to be identified in a muscular dystrophy laminin, and it is likely that these defects contribute to the abnormalities seen in dy2J/dy2J muscle and nerve.