Brain Dysfunction in LAMA2-Related Congenital Muscular Dystrophy: Lessons From Human Case Reports and Mouse Models

Abstract

Laminin α2 gene (LAMA2)-related Congenital Muscular Dystrophy (CMD) was distinguished by a defining central nervous system (CNS) abnormality-aberrant white matter signals by MRI-when first described in the 1990s. In the past 25 years, researchers and clinicians have expanded our knowledge of brain involvement in LAMA2-related CMD, also known as Congenital Muscular Dystrophy Type 1A (MDC1A). Neurological changes in MDC1A can be structural, including lissencephaly and agyria, as well as functional, including epilepsy and intellectual disability. Mouse models of MDC1A include both spontaneous and targeted LAMA2 mutations and range from a partial loss of LAMA2 function (e.g., dy^2J/dy^2J ), to a complete loss of LAMA2 expression (dy ^3K/dy ^3K). Diverse cellular and molecular changes have been reported in the brains of MDC1A mouse models, including blood-brain barrier dysfunction, altered neuro- and gliogenesis, changes in synaptic plasticity, and decreased myelination, providing mechanistic insight into potential neurological dysfunction in MDC1A. In this review article, we discuss selected studies that illustrate the potential scope and complexity of disturbances in brain development in MDC1A, and as well as highlight mechanistic insights that are emerging from mouse models.

Keywords: LAMA2; MDC1A; brain development; congenital muscular dystrophy; dystroglycanopathies; laminin.

Figure 1

The Dystrophin-Glycoprotein Complex (DGC) in skeletal muscle and its related muscular dystrophies. Abbreviations: MDC1A, Congenital Muscular Dystrophy Type 1A; LGMD, Limb-Girdle Muscular Dystrophy; DMD, Duchenne Muscular Dystrophy; BMD, Becker Muscular Dystrophy; FCMD, Fukuyama Congenital Muscular Dystrophy; MDC1C, Congenital Muscular Dystrophy Type 1C; MDC1D, Congenital Muscular Dystrophy Type 1D; WWS, Walker–Warburg Syndrome; MEB, Muscle–eye–brain disease.

Figure 2

Laminin α2 in the ventricular-subventricular zone (VZ-SVZ) neural stem cell (NSC) niche. (A) Laminin α2 influences NSC proliferation and differentiation. It influences neurogenesis and gliogenesis in the VZ-SVZ, as well as the proliferation and survival of progenitors for midbrain dopaminergic neurons. (B) Oligodendrogenesis and myelination are influenced by LAMA2 expression. In particular, LAMA2 expression influences the survival and differentiation of oligodendrocyte precursor cells (OPCs) as well as the maturation of oligodendrocytes.

Figure 3

Functional roles of laminin α2 in other areas of the central nervous system (CNS). (A) Blood-brain barrier integrity is regulated by LAMA2 expression. Inset depicts laminin interaction with dystroglycan, which helps to cluster aquaporin-4 channels at barrier astrocytic endfeet. (B) Laminin α2 influences long-term synaptic plasticity. Inset depicts laminin interaction with dystroglycan, which helps to mediate the clustering of GABA_A receptors at inhibitory synapses. (C) Neurite outgrowth and axon pathfinding are influenced by α2-containing laminins. Inset depicts laminin interaction with integrin α6β1 in neuronal growth cones, which helps to couple extracellular matrix (ECM) and the actin cytoskeleton as growth cones extend.

Figure 4

Cortical dysplasia and NSC dysfunction in Congenital Muscular Dystrophies (CMD). Left: normal cortical development. Right: abnormal cortical development in CMD. 1. Breached BM caused by mutations in DAG1 and GPR56 genes, or abnormal glycosylation by fukutin, FKRP, and LARGE1. 2. Impaired oligodendrogenesis due to loss of LAMA2 and DAG1 expression or function. 3. The detachment of NSCs due to the loss of a functional interaction between laminin α2 and β1 integrins. Inset: receptors mediate interactions between radial glial cell endfeet and with laminin α2: 1, Dystroglycan; 2, Integrin; 3, GPR56 and (possibly) GPR126. Abbreviations: BM, basement membrane; CP, cortical plate; IZ, intermediate zone; MZ/BM, Marginal Zone/Basement Membrane; NSC, neural stem cell; SVZ, subventricular zone; VZ, ventricular zone.