Laminin and Integrin in LAMA2-Related Congenital Muscular Dystrophy: From Disease to Therapeutics

Abstract

Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a devastating neuromuscular disease caused by mutations in the LAMA2 gene. These mutations result in the complete absence or truncated expression of the laminin-α2 chain. The α2-chain is a major component of the laminin-211 and laminin-221 isoforms, the predominant laminin isoforms in healthy adult skeletal muscle. Mutations in this chain result in progressive skeletal muscle degeneration as early as neonatally. Laminin-211/221 is a ligand for muscle cell receptors integrin-α7β1 and α-dystroglycan. LAMA2 mutations are correlated with integrin-α7β1 disruption in skeletal muscle. In this review, we will summarize laminin-211/221 interactions with integrin-α7β1 in LAMA2-CMD muscle. Additionally, we will summarize recent developments using upregulation of laminin-111 in the sarcolemma of laminin-α2-deficient muscle. We will discuss potential mechanisms of action by which laminin-111 is able to prevent myopathy. These published studies demonstrate that laminin-111 is a disease modifier of LAMA2-CMD through different methods of delivery. Together, these studies show the potential for laminin-111 therapy as a novel paradigm for the treatment of LAMA2-CMD.

Keywords: LAMA2-CMD; Laminin; muscle; muscular dystrophy; therapeutic; α7 integrin.

Figure 1

Molecular model in unaffected and laminin-α2-deficient patient muscle. (A) Laminin 211/221 heterotrimeric proteins bind through their N-terminal domain to the collagen-IV-rich basal lamina and through their C-terminal domain to muscle cell receptors heterodimers integrin-α7β1 and αβ-dystroglycan protein complexes. (B) In LAMA2-CMD, laminins are unable to bind to collagen-IV and/or integrin-α7β1 and α-dystroglycan protein complexes disrupting communication between the basal and muscle cell membrane.

Figure 2

Integrin-α7β1 protein complex is disrupted in laminin-α2-deficient muscle. (A) Decreased detection of integrin-α7β1 in the muscle sarcolemma in laminin-α2-truncated muscle. (B) Rescued expression of integrin-α7β1 in the muscle sarcolemma by expression of laminin-111 in laminin-α2-deficient muscle.