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

Joshua M. Kaplan, Sung Han Kim, Kathryn N. North, Helmut Rennke, Lori Ann Correia, Hui Qi Tong, Beverly J. Mathis, José Carlos Rodríguez-Pérez, Philip G. Allen, Alan H. Beggs, Martin R. Pollak

Research output: Contribution to journalArticlepeer-review

1080 Scopus citations

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 α-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 α-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type α-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.

Original languageEnglish (US)
Pages (from-to)251-256
Number of pages6
JournalNature genetics
Volume24
Issue number3
DOIs
StatePublished - Mar 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics

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