Secondary reduction of α7B integrin in laminin α2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle

The integrins are a large family of heterodimeric transmembrane cellular receptors which mediate the association between the extracellular matrix (ECM) and cytoskeletal proteins. The α7β1 integrin is a major laminin binding integrin in skeletal and cardiac muscle and is thought to be involved in myogenic differentiation and migration processes. The main binding partners of the α7 integrin are laminin-1 (α1-β1-γ1), laminin-2 (α2- β1-γ1) and laminin-4 (β2-β2-γ1). Targeted deletion of the gene for the α7 integrin subunit (ITGA7) in mice leads to a novel form of muscular dystrophy. In the present study we have investigated the expression of two alternative splice variants, the α7B and β1D integrin subunits, in normal human skeletal muscle, as well as in various forms of muscular dystrophy. In normal human skeletal muscle the expression of the α7 integrin subunit appeared to be developmentally regulated: it was first detected at 2 years of age. In contrast, the β1D integrin could be detected in immature and mature muscle in the sarcolemma of normal fetal skeletal muscle at 18 weeks gestation. The expression of α7B integrin was significantly reduced at the sarcolemma in six patients with laminin α2 chain deficient congenital muscular dystrophy (CMD) (age >2 years). However, this reduction was not correlated with the amount of laminin α2 chain expressed. In contrast, the expression of the laminin α2 chain was not altered in the skeletal muscle of the a7 knock-out mice. These data argue in favor that there is not a fight correlation between the expression of the α7 integrin subunit and that of the laminin α2 chain in either human or murine dystrophic muscle. Interestingly, in dystrophinopathies (Duchenne and Becker muscular dystrophy; DMD/BMD) expression of α7B was upregulated irrespective of the level of dystrophin expression as shown by a strong sarcolemmal staining pattern even in young boys (age <2 years). The expression of the β1D integrin subunit was not altered in any of our patients with different types of muscular dystrophy. In contrast, sarcolemmal expression of β1D integrin was significantly reduced in the α7 integrin knock-out mice, whereas the expression of the components of the DGC was not altered. The secondary loss of α7B in laminin α2 chain deficiency defines a biochemical change in the composition of the plasma membrane resulting from a primary protein deficiency in the basal lamina. These findings, in addition to the occurrence of a muscular dystrophy in α7 deficient mice, implies that the α7B integrin is an important laminin receptor within the plasma membrane which plays a significant role in skeletal muscle function and stability.