title: Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.
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.
authors.affiliation: Renal and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Kaplan
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: K N
authors.initials: KN
authors.lastname: North
authors.forename: H
authors.initials: H
authors.lastname: Rennke
authors.forename: L A
authors.initials: LA
authors.lastname: Correia
authors.forename: H Q
authors.initials: HQ
authors.lastname: Tong
authors.forename: B J
authors.initials: BJ
authors.lastname: Mathis
authors.forename: J C
authors.initials: JC
authors.lastname: Rodríguez-Pérez
authors.forename: P G
authors.initials: PG
authors.lastname: Allen
authors.forename: A H
authors.initials: AH
authors.lastname: Beggs
authors.forename: M R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000185:Actinin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C111453:ACTN4 protein, human; D000199:Actins; D008840:Microfilament Proteins; D000185:Actinin