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


Focal and segmental glomerulosclerosis1 (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.

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Figure 1: FSGS pedigrees and FSGS-1 locus.
Figure 2: Kidney biopsies.
Figure 3: Mutational analysis.
Figure 4: α-Actin sequence alignment.
Figure 5: Analysis of α-actinin-4 expression.
Figure 6: Actin-binding experiments.

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We thank the family members for participation; members of the Department of Genetics, Harvard Medical School and the Department of Medicine at Brigham and Women's Hospital, particularly B. Denker, for helpful discussions; A. Shahsafaei for help with immunofluorescence; L. Ashworth for help with chromosome 19 sequence informatics; M. Dolliver for help with clinical ascertainment; and members of the core sequencing facilities and the Genome Center at the Brigham and Women's Hospital for their assistance. This work was supported by NIH grants DK54931 (M.R.P.), AR44345 and AR02026 (A.H.B.), GM57256 (P.G.A.) and a National Research Service Award (J.M.K.), as well as grants from the National Kidney Foundation and the Burroughs Wellcome Fund (M.R.P.) and the Muscular Dystrophy Association (A.H.B.).

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Correspondence to Martin R. Pollak.

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Kaplan, J., H Kim, S., North, K. et al. Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24, 251–256 (2000).

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