Gene disruption of dematin causes precipitous loss of erythrocyte membrane stability and severe hemolytic anemia

Abstract

• Genetic deletion of full-length mouse dematin causes severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia.• Dematin is critical for the junctional complex integrity.Dematin is a relatively low abundance actin binding and bundling protein associated with the spectrin-actin junctions of mature erythrocytes. Primary structure of dematin includes a loosely folded core domain and a compact headpiece domain that was originally identified in villin. Dematin's actin binding properties are regulated by phosphorylation of its headpiece domain by cyclic adenosine monophosphate-dependent protein kinase.Here, we used a novel gene disruption strategy to generate the whole body dematin gene knockout mouse model (FLKO). FLKO mice, while born at a normal Mendelian ratio, developed severe anemia and exhibited profound aberrations of erythrocyte morphology and membrane stability. Having no apparent effect on primitive erythropoiesis, FLKO mice show significant enhancement of erythroblast enucleation during definitive erythropoiesis. Using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements, we investigated the mechanism of membrane instability in FLKO erythrocytes. Although many membrane and cytoskeletal proteins remained at their normal levels, the major peripheral membrane proteins spectrin, adducin, and actin were greatly reduced in FLKO erythrocytes. Our results demonstrate that dematin plays a critical role in maintaining the fundamental properties of the membrane cytoskeleton complex. (Blood. 2016;128(1):93-103)

Profiling Gene Programs in the Blood During Liver Regeneration in Living Liver Donors

“…Other erythroid‐selective genes included aminolevulinate synthase 2 (ALAS2; 5.3‐fold) and erythroid Kruppel‐like factor (KLF) 1 (2.8‐fold), which mediate erythrocyte differentiation . Also up‐regulated were dematin actin binding protein (DNMNT; 2.7‐fold) and EBP42 (3.5‐fold), which maintain the structural integrity and function of erythrocytes . Moreover, several hemoglobin (Hb) subunit genes were induced (Table ).…”

Circulating primitive erythroblasts establish a functional, protein 4.1R-dependent cytoskeletal network prior to enucleating

“…In contrast, the normal morphology of E13.5 dematin-null primitive erythroblasts led to the speculation that dematin lacks a role in primitive erythropoiesis 38 . However, functional studies of primitive erythroblasts were not performed.…”

MPP1/p55 gene deletion in a hemophilia A patient with ectrodactyly and severe developmental defects

“…10 The membrane protein composition was examined by gel electrophoresis and a complete loss of MPP1 protein expression was observed by Western blotting using a monoclonal antibody against MPP1 ( Figure 1E,F, arrowhead). 10 The membrane protein composition was examined by gel electrophoresis and a complete loss of MPP1 protein expression was observed by Western blotting using a monoclonal antibody against MPP1 ( Figure 1E,F, arrowhead).…”