Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis.
The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif-containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLCε1, the identification of mutations that may alter the putative INF2-IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS.
INSERM U983, Tour Lavoisier, 6 étage, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
Olivia
O
Boyer
Geneviève
G
Benoit
Olivier
O
Gribouval
Fabien
F
Nevo
Marie-Josèphe
MJ
Tête
Jacques
J
Dantal
Brigitte
B
Gilbert-Dussardier
Guy
G
Touchard
Alexandre
A
Karras
Claire
C
Presne
Jean-Pierre
JP
Grunfeld
Christophe
C
Legendre
Dominique
D
Joly
Philippe
P
Rieu
Nabil
N
Mohsin
Thierry
T
Hannedouche
Valérie
V
Moal
Marie-Claire
MC
Gubler
Isabelle
I
Broutin
Géraldine
G
Mollet
Corinne
C
Antignac
D000185:Actinin / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D000080865:Formins; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000235:genetics*; D006801:Humans; D007223:Infant; D008840:Microfilament Proteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020703:ras GTPase-Activating Proteins / Q000502:physiology
C111453:ACTN4 protein, human; D000080865:Formins; C546959:INF2 protein, human; C101203:IQ motif containing GTPase activating protein 1; D008840:Microfilament Proteins; D020703:ras GTPase-Activating Proteins; D000185:Actinin
EMBO J. 2005 Dec 7;24(23):4176-87
16292343
Nat Protoc. 2009;4(3):363-71
19247286
Nat Genet. 2010 Jan;42(1):72-6
20023659
Nucleic Acids Res. 1990 Jun 11;18(11):3227-31
1972560
J Cell Biol. 1997 Jun 30;137(7):1555-66
9199170
J Cell Sci. 2009 May 1;122(Pt 9):1430-40
19366733
Annu Rev Biochem. 2007;76:593-627
17373907
Nat Genet. 2006 Dec;38(12):1397-405
17086182
J Cell Biol. 2007 Jul 16;178(2):193-200
17620407
Hum Mol Genet. 2009 Oct 15;18(R2):R185-94
19808795
Am J Kidney Dis. 1998 Jul;32(1):72-9
9669427
J Biol Chem. 2006 Sep 8;281(36):26754-67
16818491
Science. 2005 Jun 17;308(5729):1801-4
15879175
Nephrol Dial Transplant. 2009 Oct;24(10):3089-96
19458060
Nat Genet. 2005 Jul;37(7):739-44
15924139
PLoS One. 2009 Nov 10;4(11):e7771
19936226
J Am Soc Nephrol. 2005 Dec;16(12):3694-701
16251236
Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9814-9
15994232
Nature. 1980 Oct 9;287(5782):560-1
6999365
Mol Cell. 1998 Mar;1(4):575-82
9660941