α-actinin-4-mediated fsgs an inherited kidney disease caused by an aggregated and rapidly degraded cytoskeletal proteinα-actinin-4-mediated fsgs一种遗传性肾脏疾病引起的聚合和迅速退化的细胞骨架蛋白.pdfVIP

PLoS BIOLOGY a-Actinin-4-Mediated FSGS: An Inherited Kidney Disease Caused by an Aggregated and Rapidly Degraded Cytoskeletal Protein 1 1 1 2 3 1 1* June Yao , Tu Cam Le , Claudine H. Kos , Joel M. Henderson , Phillip G. Allen , Bradley M. Denker , Martin R. Pollak 1 Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, 2 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, 3 Hematology Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America Focal segmental glomerulosclerosis (FSGS) is a common pattern of renal injury, seen as both a primary disorder and as a consequence of underlying insults such as diabetes, HIV infection, and hypertension. Point mutations in the a-actinin-4 gene ACTN4 cause an autosomal dominant form of human FSGS. We characterized the biological effect of these mutations by biochemical assays, cell-based studies, and the development of a new mouse model. We found that a fraction of the mutant protein forms large aggregates with a high sedimentation coefficient. Localization of mutant a-actinin-4 in transfected and injected cells, as well as in situ glomeruli, showed aggregates of the mutant protein. Video microscopy showed the mutant a-actinin-4 to be markedly less dynamic than the wild-type protein. We developed a ‘‘knockin’’ mouse model by replacing Actn4 with a copy of the gene bearing an FSGS-associated point mutation. We used