Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-α2 chain-deficient congenital muscular dystrophy

Abstract

Congenital muscular dystrophy (CMD) is a class of severe early-onset muscular dystrophies affecting skeletal/cardiac muscles as well as the central nervous system (CNS). Laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2 MD), also known as merosin-deficient congenital muscular dystrophy type 1A (MDC1A), is an autosomal recessive CMD characterized by severe muscle weakness and degeneration apparent at birth or in the first 6 months of life. LAMA2 MD is the most common congenital muscular dystrophy, affecting approximately 4 in 500,000 children. The most common cause of death in early-onset LAMA2 MD is respiratory tract infection, with 30% of them dying within the first decade of life. LAMA2 MD is caused by loss-of-function mutations in the LAMA2 gene encoding for the laminin-α2 chain, one of the subunits of laminin-211. Laminin-211 is an extracellular matrix protein that functions to stabilize the basement membrane and muscle fibers during contraction. Since laminin-α2 is expressed in many tissue types including skeletal muscle, cardiac muscle, Schwann cells, and trophoblasts, patients with LAMA2 MD experience a multi-systemic clinical presentation depending on the extent of laminin-α2 chain deficiency. Cardiac manifestations are typically associated with a complete absence of laminin-α2; however, recent case reports highlight cardiac involvement in partial laminin-α2 chain deficiency. Laminin-211 is also expressed in the brain, and many patients have abnormalities on brain imaging; however, mental retardation and/or seizures are rarely seen. Currently, there is no cure for LAMA2 MD, but various therapies are being investigated in an effort to lessen the severity of LAMA2 MD. For example, antisense oligonucleotide-mediated exon skipping and CRISPR-Cas9 genome editing have efficiently restored the laminin-α2 chain in mouse models in vivo. This review consolidates information on the clinical presentation, genetic basis, pathology, and current treatment approaches for LAMA2 MD.

Keywords: CRISPR/Cas9; LAMA2; exon skipping; genome editing; non-homologous end joining; phosphorodiamidate morpholino oligomer.

Figure 1

(A) Laminin-α2 and the dystrophin glycoprotein complex. Laminin-α2 interacts with the laminin β and γ chains to form laminin-211, which binds both α-dystroglycan (α-DG) and the α7β1 integrin. Other members of the dystrophin glycoprotein complex are also depicted, with the dystrophin domains shown. β-DG, β-dystroglycan; SPN: sarcospan. (B) Therapeutic strategies developed for LAMA2 MD. An overview of the various LAMA2 MD treatments (in yellow boxes) is shown. For the LAMA2 gene and pre-mRNA diagrams depicted, a red “X” represents the location of the indicated mouse model mutation. Abbreviations: CMD, congenital muscular dystrophy; CNS, central nervous system; LAMA2 MD, Laminin-α2 chain-deficient muscular dystrophy; MDC1A, merosin-deficient congenital muscular dystrophy type 1A; NHEJ, nonhomologous end-joining; PMO, phosphorodiamidate morpholino oligomer; ECM, extracellular matrix; CK, creatine kinase; ECG, electrocardiography; EF, ejection fraction; SMA, spinal muscular atrophy; DGC, dystrophin-glycoprotein complex; LG, laminin G; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; TA, tibialis anterior; α2LN, laminin-α2 N-terminal domain; MCK, muscle creatine kinase; CNF centrally nucleated fiber; EHS, Engelbreth-Holm-Swarm; IGF-1, insulin-like growth factor 1; EDL, extensor digitorum longus; SOL, soleus; MLC, myosin light chain; TGF-β1, transforming growth factor β1; AO, antisense oligonucleotide; DMD, Duchenne muscular dystrophy.