Abstract
Laminin-211 is a cell-adhesion molecule that is strongly expressed in the basement membrane of skeletal muscle. By binding to the cell surface receptors dystroglycan and integrin α7β1, laminin-211 is believed to protect the muscle fiber from damage under the constant stress of contractions, and to influence signal transmission events. The importance of laminin-211 in skeletal muscle is evident from merosin-deficient congenital muscular dystrophy type 1A (MDC1A), in which absence of the α2 chain of laminin-211 leads to skeletal muscle dysfunction. MDC1A is the commonest form of congenital muscular dystrophy in the European population. Severe hypotonia, progressive muscle weakness and wasting, joint contractures and consequent impeded motion characterize this incurable disorder, which causes great difficulty in daily life and often leads to premature death. Mice with laminin α2 chain deficiency have analogous phenotypes, and are reliable models for studies of disease mechanisms and potential therapeutic approaches. In this review, we introduce laminin-211 and describe its structure, expression pattern in developing and adult muscle and its receptor interactions. We will also discuss the molecular pathogenesis of MDC1A and advances toward the development of treatment.
Highlights
The basement membrane is a thin scaffold of specific extracellular protein networks associated with various cell types, including muscle fibers
The trimers are named according to the composition of the a, b and g chains and more than 15 different laminin isoforms, with various arrangements of laminin subunits, have been identified [3,4,5]
It is well established that laminin-211 is the main laminin isoform in skeletal muscle [8,9], and identification of laminin a2 chain mutations in a severe form of congenital muscular dystrophy showed the importance of laminin-211 for normal muscle function [10]
Summary
The basement membrane is a thin scaffold of specific extracellular protein networks associated with various cell types, including muscle fibers. Two further mouse models have been generated by homologous recombination: the dyW/dyW mouse expresses small amounts of a truncated a2 chain lacking the LN domain whereas the dy3K/dy3K mouse (Figure 5) is completely deficient in the laminin a2 chain Both dyW/dyW and dy3K/dy3K mice develop severe muscular dystrophy and die within a few weeks of age. The most recently described mouse model is the dynmj417/dynmj417 mouse, in which a single point mutation in the LN domain leads to normal levels of a mutated laminin a2 chain and mild muscular dystrophy [87] It can be debated whether mice are reliable as preclinical models for human disease, analyses of the various laminin a2 chain-deficient mouse models have led to a significant improvement in our understanding of development of MDC1A. Inactivation of Bax s [114] and treatment with doxycycline [116] were reported to be beneficial for the condition of motor neuron
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