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Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis

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Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis BRIEF COMMUNICATION www.jasn.org Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis ʈ Olivia Boyer,*†‡§ Genevie`ve Benoit,* Olivier Gribouval,* Fabien Nevo,* Marie-Jose`phe Teˆte,* Jacques Dantal,¶ Brigitte Gilbert-Dussardier,** Guy Touchard,†† ʈʈ Alexandre Karras,‡‡‡ Claire Presne,§§ Jean-Pierre Grunfeld,‡ Christophe Legendre,‡¶¶ ʈʈ Dominique Joly,‡ Philippe Rieu,*** Nabil Mohsin,††† Thierry Hannedouche,‡‡‡ ʈʈʈ Vale´rie Moal,§§§ Marie-Claire Gubler,* Isabelle Broutin,‡ Ge´raldine Mollet,* and Corinne Antignac*‡§ BRIEF COMMUNICATIONS *INSERM U983, Hoˆpital Necker-Enfants Malades, Paris, France; †Service de Ne´phrologie Pe´diatrique and §De´partement de Ge´ne´ tique, Centre de Re´fe´ rence MARHEA, Hoˆpital Necker-Enfants Malades, Assistance Publique-Hoˆpitaux de Paris ʈ (APHP), Paris, France; ‡Universite´ Paris Descartes, Faculte´deMe´ decine Paris Descartes, Paris, France; Service de Ne´phrologie Pe´diatrique, CHU Sainte-Justine, Universite´ de Montre´al, Montre´al, Que´bec, Canada; ¶Service de Ne´phrologie et Immunologie Clinique, ITERT, CHU Hoˆtel Dieu, Nantes, France; **Service de Ge´ne´ tique Me´dicale and ††Service de Ne´phrologie, CHU La Mile´trie, Poitiers, France; ‡‡Service de Ne´phrologie, Hoˆpital Europe´en Georges Pompidou, APHP, Paris, France; §§Service de Ne´phrologie-Me´decine Interne, CHU d’Amiens, Hoˆpital Sud, Amiens, ʈʈ France; Service de Ne´phrologie and ¶¶Service de Transplantation Re´nale, Hoˆpital Necker-Enfants Malades, APHP, Paris, France; ***Service de Ne´phrologie, Hoˆpital du Kremlin-Biceˆtre, APHP, Le Kremlin-Biceˆtre, France; †††Department of Nephrology, Royal Hospital, Muscat, Oman; ‡‡‡AURAL et Service de Ne´phrologie, Hoˆpitaux Universitaires de Strasbourg, Strasbourg, France; §§§Centre de Ne´phrologie et de Transplantation Re´nale, Hoˆpital de la Conception, ʈʈʈ APHM, Marseille, France; and Laboratoire de Cristallographie et RMN Biologiques, CNRS, UMR, Paris, France ABSTRACT The recent identification of mutations in the INF2 gene, which encodes a member human genes highly expressed in podo- of the formin family of actin-regulating proteins, in cases of familial FSGS supports cytes have been identified to cause this the importance of an intact actin cytoskeleton in podocyte function. To determine entity2; these findings highlighted the better the prevalence of INF2 mutations in autosomal dominant FSGS, we crucial role of the podocyte in the glo- screened 54 families (78 patients) and detected mutations in 17% of them. All merular filtration barrier function. Al- mutations were missense variants localized to the N-terminal diaphanous inhibitory though an autosomal recessive inheri- domain of the protein, a region that interacts with the C-terminal diaphanous tance underlies most cases of inherited autoregulatory domain, thereby competing for actin monomer binding and inhib- FSGS occurring in childhood, a few iting depolymerization. Six of the seven distinct altered residues localized to an genes have been shown to be involved in INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory the rare autosomal dominant (AD) juve- domain reported to co-immunoprecipitate with IQ motif–containing GTPase-acti- nile and adult forms of the disease. In- vating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but de- deed, mutations in ACTN4, encoding tected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podo- cyte proteins such as nephrin and PLC␧1, the identification of mutations that may Received May 19, 2010. Accepted August 30, 2010. alter the putative INF2–IQGAP1 interaction provides additional insight into the Published online ahead of print. Publication date pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and available at www.jasn.org. FSGS. O.B., G.B., and O.G. contributed equally to this work and should be considered joint first authors. J Am Soc Nephrol 22: 239–245, 2011. doi: 10.1681/ASN.2010050518 Correspondence: Dr. Corinne Antignac, INSERM U983, Tour Lavoisier, 6e e´tage, Hoˆpital Necker-En- fants Malades, 149 rue de Se`vres, 75015 Paris, France. Phone: ϩ33-1-44-49-51-02; Fax: ϩ33-1-44- FSGS is a histologic pattern of injury of isolated proteinuria/nephrotic syn- 49-02-90; E-mail: [email protected] 1 leading to end-stage kidney disease drome. The recognition of familial Copyright © 2011 by the American Society of (ESKD) in approximately 40% of cases forms of FSGS has grown, and several Nephrology J Am Soc Nephrol 22: 239–245, 2011 ISSN : 1046-6673/2202-239 239 BRIEF COMMUNICATION www.jasn.org ␣-actinin 4, and TRPC6, encoding a suggested that INF2 may play a signifi- and ESKD. For example, in family A, car- member of the transient receptor poten- cant role in FSGS, this finding has not yet rying the p.L76P mutation, one member tial superfamily of ion channels, have been confirmed by others. In addition, required dialysis at the age of 28 years been identified in patients presenting the role of INF2 mutations among cases whereas another presented moderate pro- late-onset proteinuria with a slow pro- with a sporadic appearance has never teinuria without ESKD at the age of 79 gression to ESKD and may account for been evaluated. We therefore aimed to years. approximately 4 and 6% of familial determine the prevalence of INF2 muta- Given the occurrence of incomplete FSGS, respectively.3–7 Whereas the dis- tions in a cohort of 54 families (78 pa- penetrance in AD FSGS cases and the covery of TRPC6 unexpectedly sugges- tients) with a glomerular proteinuric dis- reports of neomutation in ACTN4-, ted the implication of calcium signaling order of apparent AD inheritance. These TRPC6-, and INF2-related FSGS,3,6,8 we in the pathogenesis of FSGS, the identifi- patients presented proteinuria at a me- undertook the search for INF2 muta- cation of ACTN4 emphasized the impor- dian age of 20.5 years (range 2 to 52 tions in 84 sporadic cases. The clinical tance of an intact podocyte actin cy- years), and FSGS was documented in at presentation of sporadic and familial toskeleton in kidney function. least one affected member in 80% of cases was similar. Only one already iden- Recently, Brown et al.8 found het- families (Table 1). tified mutation (p.R218Q) was detected erozygous mutations in the formin INF2 Seven missense INF2 mutations were in a single patient, who presented pro- gene segregating with FSGS in 11 (12%) found in nine families (28 patients), teinuria and FSGS lesions at 15 years of of 93 families with age at diagnosis and which translates to a detection rate of age. However, a complete renal evalua- ESKD varying from 11 to 72 years and 13 16.7% (Table 2). Median age at onset of tion and DNA samples were not available to 67 years, respectively. Formins are proteinuria among mutated patients was for his seemingly healthy parents, pre- widely expressed proteins governing sev- 27 years (compared with 15.5 years cluding the distinction between a de novo eral dynamic events that require remod- among familial cases without mutations; mutation and a familial case with low eling of the actin cytoskeleton such as cell P ϭ 0.026); proteinuria was isolated and penetrance and variable expressivity. polarity, cell and tissue morphogenesis, in the nephrotic range (at least tran- Among the seven mutations identi- and cytokinesis.9 To date, 15 mammalian siently) for most cases. Full-blown ne- fied in familial cases, four were novel formin genes have been identified, phrotic syndrome was noted in four pa- mutations. We detected the p.R218Q among which are the best studied diaph- tients. Median age at ESKD was 36 years and p.E220K in families from France, anous-related formins (DRF)—mDia1, (range 20 to 70 years). No significant sta- and these substitutions were also previ- mDia2, and mDia3—but also the in- tistical difference was observed regarding ously identified in families from the verted formins (INF). In the C-terminal the percentage of patients reaching United States (European ancestry).8 In half, DRF proteins contain the formin ESKD (P ϭ 0.085) and the age at onset of addition, we found the p.R177H and the homology domains FH1/FH2 and the ESKD (P ϭ 0.629) between familial cases p.R214C mutations each in two seem- diaphanous autoregulatory domain with or without mutations. FSGS was ingly nonrelated families (from France). (DAD) region, whereas the diaphanous documented in at least one affected We studied a possible founder effect by inhibitory domain (DID) is localized at member of each family with INF2 muta- haplotype analysis using six markers the N-terminal half. The FH2 domain di- tion. Mutations segregated with disease flanking the locus. No common ancestral rectly mediates actin assembly, and the in each respective family, although the disease-associated haplotype was found, FH1 domain accelerates, through profi- screening of seven additional at-risk suggesting no founder effect (data not lin-actin complexes, filament elonga- asymptomatic relatives (from three fam- shown). All these four single-base mu- tion. Interaction between DID and DAD ilies) revealed a mutation in two cases, tations involve a CpG dinucleotide, blocks the ability of the FH2 to interact confirming the incomplete penetrance of consistent with a chemical model of with actin, and this inhibition is relieved the disease (Supplemental Figure S1). In- mutation via methylation-mediated by the Rho GTPases.10 In contrast to deed, in family F carrying the p.R214C, deamination.13 Because this represents other formins, INF2-mediated polymer- one affected member presented protein- by far the most common single-base ization is not inhibited by the DID–DAD uria at 5 years of age whereas a relative substitution involved in human dis- interaction. In addition, INF2 has the was still free of renal manifestations at 26 ease,14 we can speculate that these mu- unique ability to accelerate depolymer- years of age.
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