Abnormal Expression of Laminin 1 Chain in Skeletal Muscle of Adult-Onset Limb-Girdle Muscular Dystrophy

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Abstract
Background: Laminin 2 is a major component of the basal lamina of skeletal muscle cells. It is a heterotrimer composed of 3 chains: merosin (laminin α2 chain), β1, and γ1. Deficiency of merosin, with or without laminin β1 chain reduction, is associated with some forms of congenital muscular dystrophy. Deficient expression of laminin β1 chain is also associated with some cases of merosin-positive congenital muscular dystrophy. The expression of laminin 2 subunits has not been well studied in the skeletal muscle of limb-girdle muscular dystrophy (LGMD), nor has much attention been given to the significance of reduction of individual laminin 2 subunits, such as β1. Objectives: To examine the expression of laminin 2 subunits in skeletal muscle in patients with LGMD and to define the clinical features of patients with LGMD who have abnormal expression of laminin 2 subunits. Methods: We studied muscle biopsy specimens from 18 patients with LGMD using immunofluorescence with antibodies against dystrophin C-terminus, β-dystroglycan, α-sarcoglycan, γ-sarcoglycan, and the laminin subunits merosin, β1, and γ1. Of the 18 biopsy specimens, 9 were available for electron microscopic examination of the muscle basement membrane. The clinical features associated with abnormal laminin β1 chain immunoreactivity were further described. Results: Laminin β1 chain was either barely detectable or severely reduced in 3 cases of patients with LGMD in which the biopsy specimens showed normal staining with the other antibodies. Patients in all 3 cases had common clinical features consistent with a slowly progressive, adultonset LGMD. Specimens from 2 of the 3 cases that were available for ultrastructural examination showed significant abnormalities of the muscle fiber basement membrane. Conclusions: Abnormal expression of laminin β1 chain without concomitant deficiency of α-sarcoglycan in skeletal muscle has not been previously described in LGMD. Reduced laminin β1 chain immunoreactivity may potentially serve as a marker for defining subsets of individuals with LGMD, in particular those with slowly progressive, adult-onset pelvifemoral presentation. The abnormality of muscle fiber basement membranes in specimens from cases that were available for ultrastructural study suggests that defects in the extracellular matrix may play a role in the pathogenesis of this subset of LGMD.