Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis.
Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury observed either as an idiopathic finding or as a consequence of underlying systemic conditions. Several genes have been identified that, when mutated, lead to inherited FSGS and/or the related nephrotic syndrome. These findings have accelerated the understanding of glomerular podocyte function and disease, motivating our search for additional FSGS genes. Using linkage analysis, we identified a locus for autosomal-dominant FSGS susceptibility on a region of chromosome 14q. By sequencing multiple genes in this region, we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.
Brown
Elizabeth J
EJ
Renal Division, Children's Hospital, Boston, Massachusetts, USA.
Schlöndorff
Johannes S
JS
Becker
Daniel J
DJ
Tsukaguchi
Hiroyasu
H
Tonna
Stephen J
SJ
Uscinski
Andrea L
AL
Higgs
Henry N
HN
Henderson
Joel M
JM
Pollak
Martin R
MR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D000080865:Formins; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D008854:Microscopy, Electron; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
D000080865:Formins; C546959:INF2 protein, human; D008840:Microfilament Proteins