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      Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.

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          Abstract

          Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.

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          Author and article information

          Journal
          Nat Genet
          Nature genetics
          Springer Science and Business Media LLC
          1061-4036
          1061-4036
          Mar 2000
          : 24
          : 3
          Affiliations
          [1 ] Renal and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
          Article
          10.1038/73456
          10700177
          7ece7ae3-2992-4489-984f-f10e25191401
          History

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