title: Secondary reduction of alpha7B integrin in laminin alpha2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle.
abstract: The integrins are a large family of heterodimeric transmembrane cellular receptors which mediate the association between the extracellular matrix (ECM) and cytoskeletal proteins. The alpha7beta1 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 alpha7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1). Targeted deletion of the gene for the alpha7 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 alpha7B and beta1D 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 alpha7 integrin subunit appeared to be developmentally regulated: it was first detected at 2 years of age. In contrast, the beta1D integrin could be detected in immature and mature muscle in the sarcolemma of normal fetal skeletal muscle at 18 weeks gestation. The expression of alpha7B integrin was significantly reduced at the sarcolemma in six patients with laminin alpha2 chain deficient congenital muscular dystrophy (CMD) (age >2 years). However, this reduction was not correlated with the amount of laminin alpha2 chain expressed. In contrast, the expression of the laminin alpha2 chain was not altered in the skeletal muscle of the alpha7 knock-out mice. These data argue in favor that there is not a tight correlation between the expression of the alpha7 integrin subunit and that of the laminin alpha2 chain in either human or murine dystrophic muscle. Interestingly, in dystrophinopathies (Duchenne and Becker muscular dystrophy; DMD/BMD) expression of alpha7B 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 beta1D integrin subunit was not altered in any of our patients with different types of muscular dystrophy. In contrast, sarcolemmal expression of beta1D integrin was significantly reduced in the alpha7 integrin knock-out mice, whereas the expression of the components of the DGC was not altered. The secondary loss of alpha7B in laminin alpha2 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 alpha7 deficient mice, implies that the alpha7B integrin is an important laminin receptor within the plasma membrane which plays a significant role in skeletal muscle function and stability.
authors.affiliation: Department of Pediatrics, University of Essen, Germany.
authors.forename: R D
authors.initials: RD
authors.lastname: Cohn
authors.forename: U
authors.initials: U
authors.lastname: Mayer
authors.forename: G
authors.initials: G
authors.lastname: Saher
authors.forename: R
authors.initials: R
authors.lastname: Herrmann
authors.forename: A
authors.initials: A
authors.lastname: van der Flier
authors.forename: A
authors.initials: A
authors.lastname: Sonnenberg
authors.forename: L
authors.initials: L
authors.lastname: Sorokin
authors.forename: T
authors.initials: T
authors.lastname: Voit
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics; D049030:Dystroglycans; D016189:Dystrophin / Q000235:genetics; D005314:Embryonic and Fetal Development; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D039001:Integrin alpha Chains; D016023:Integrins / Q000235:genetics; D007797:Laminin / Q000172:deficiency* / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000196:embryology / Q000254:growth & development / Q000503:physiopathology*; D009136:Muscular Dystrophies / Q000151:congenital / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D049031:Sarcoglycans
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D016189:Dystrophin; D039001:Integrin alpha Chains; D016023:Integrins; D007797:Laminin; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D049031:Sarcoglycans; C085725:integrin alpha7; C102645:laminin alpha 2; D049030:Dystroglycans