O'Brien, B.; Oliver, J.; Thompson, E. N.; Mayday, M. Y.; Mancuso, R.; Jha, A.; Kwan, J.; Bonne, G.; Ben Yaou, R.; Leturcq, F.; Bai, S.; Nottoli, T.; Hwa, J.; Krause, D. S.; Gallagher, P. G.; Gu, S. X.; Martin, K. A.

Red blood cells (RBC) are essential for the survival of aerobic organisms. Mutations in RBC plasma membrane proteins can give rise to a spectrum of diseases characterized by hemolysis, inefficient gas exchange, and anemia. We tested whether emerin (EMD), a nuclear envelope (NE) protein, is also expressed in anuclear cell types to regulate membrane structure and function. We find that emerin is localized to the RBC plasma membrane and regulates the localization of other membrane proteins involved in actin branching and cytoskeletal dynamics. Additionally, we find that loss of Emd in mice results in decreased RBC corpuscular volume and hemoglobin content in both sexes, as well as a male-specific increase in RBC number and hematocrit, consistent with other male-dominated EMD phenotypes. Along with decreased RBC size, we observed a reduction in the rate of osmotic lysis in Emd KO animals, particularly males. We found that human EMD mutations also have a statistically significant association with RBC phenotypes, namely MCV. Individuals with emerin-related Emery-Dreifuss muscular dystrophy (EDMD) also demonstrate a mild yet consistent RBC phenotype according to patient CBC data. Together, these data suggest that emerin can have cell-specific localization and functions independent of its canonical repertoire in nucleated cells.