Molecular Pathogenesis of Genetic and Inherited Diseases Dysferlin Deficiency Enhances Monocyte Phagocytosis A Model for the Inflammatory Onset of Limb-Girdle Muscular Dystrophy 2B

Dysferlin deficiency causes limb-girdle muscular dys-trophy type 2B (LGMD2B; proximal weakness) and Miyoshi myopathy (distal weakness). Muscle inflam-mation is often present in dysferlin deficiency, and patients are frequently misdiagnosed as having poly-myositis. Because monocytes normally express dys-ferlin, we hypothesized that monocyte/macrophage dysfunction in dysferlin-deficient patients might con-tribute to disease onset and progression. We therefore examined phagocytic activity, in the presence and absence of cytokines, in freshly isolated peripheral blood monocytes from LGMD2B patients and in the SJL dysferlin-deficient mouse model. Dysferlin-defi-cient monocytes showed increased phagocytic activ-ity compared with control cells. siRNA-mediated inhi