INF2 Is Another Piece of the Jigsaw Puzzle for FSGS
Authors: York Pei
Journal: Journal of the American Society of Nephrology (2011)

Idiopathic FSGS is a syndrome of both immunologic and nonimmunologic etiologies often leading to ESRD.1,2 It is recognized typically by the presence of nephrotic syndrome in association with several varieties of glomerular lesions on light and electron microscopy, which individually are not very specific.3 Up to 40% of patients with FSGS experience a complete remission of their proteinuria in response to treatment with immunosuppressive drugs and have an excellent renal prognosis.2 By contrast, unresponsive patients with high-grade proteinuria are at significant risk for renal progression. There is no reliable means to differentiate between the immune and nonimmune forms of FSGS. Consequently, there is much uncertainty as to the use of immunosuppressive agents (when, if at all, and how much) in FSGS among the clinicians who have to balance the risk of unwanted toxicities from aggressive treatment in patients who might not respond versus the risk for ESRD with inadequate treatment in patients who would. In this era of molecular medicine, we have also witnessed significant progress in understanding the genetic basis of disease with the hope that this new knowledge will improve diagnostic recognition and mechanism-based therapeutics. To this end, FSGS is also being redefined at the molecular level. By positional cloning, nephrin (NPHS1) was the first gene shown to cause a severe form of congenital nephrotic syndrome.4 Using the same strategy, three recessive (NPHS2, CD2AP, and PLCE1)5–7 and three dominant (ACTN4, TRPC6, and INF2)8–11 disease genes to date have been identified as causes of nonsyndromic forms of familial FSGS. These studies highlight the central role of podocyte dysfunction in the molecular pathogenesis of proteinuric disorders.12,13 Specifically, we now know that nephrin, podocin, CD2AP, the protein products of NPHS1, NPHS2, and CD2AP, respectively, are the main structural elements of the glomerular slit diaphragm.12 TRPC6, encoded by TRPC6, is a calcium channel localized in the membrane lipid complex with podocin that regulates the mechanosensation of the slit diaphragm.10 PLCε1, encoded by PLCE1, is a phospholipase that interacts with nephrin and IQGAP-1, a podocyte cell junction–associated protein.7 By contrast, altered actin bundling seems to play a pathogenic role in familial FSGS associated with ACTN4 mutations.8 To this we now add the recent discovery that mutations of INF2 also cause a form of familial FSGS.11 Inverted formin 2 (INF2) is a member of the diaphanous formin subfamily of actin-regulating proteins that sever actin filaments and accelerate actin polymerization and depolymerization.14 Characteristic of the diaphanous formins, INF2 is regulated by autoinhibition through interaction of an N-terminus diaphanous inhibitory domain and a C-terminus diaphanous autoregulatory domain. Interestingly, all of the missense mutations reported by Brown et al.11 in their families with FSGS and confirmed by Boyer et al.15 in this issue of JASN are located within the diaphanous inhibitory domain region. More recently, a preliminary report by Akilesh et al.16 suggested that a mutation of ARHGAP24, which encodes a negative regulator of Rho GTPases implicated in actin remodeling, cell polarity, and cell migration, may also cause familial FSGS. Collectively, the latter findings on ACTN4, INF2, and ARHGAP24 suggest an important role of cytoskeletal dynamics in the normal maintenance of podocyte function. What are the clinical correlates of these disease mutations? In general, recessive mutations in NPHS2, CD2AP, and PLCE1 associate with more severe disease with earlier onset proteinuria and ESRD presenting in infancy and throughout childhood, although some milder cases have also been noted.5–7,13 By contrast, dominant mutations in ACTN4, TRPC6, and INF2 associate with milder disease with later onset proteinuria in the second decade and ESRD in the third and fourth decades of life.8–11,13,15 On renal biopsy, both minimal change lesions and FSGS may be found in different affected members from the same family.13,17 With the exception of NPHS2 and INF2, which account for up to approximately 40% and approximately 15% of childhood- and adult-onset familial FSGS, respectively, all of the other disease gene mutations account for only a small fraction of familial FSGS.5–13,15 Similarly, with the exception of NPHS2, which may account for 6 to 17% of sporadic childhood-onset FSGS, all of the other disease gene mutations are quite rare in sporadic FSGS.5–13,15 Looking forward, what can we expect to see in future studies of familial FSGS? It is likely that multiple rare disease genes with large effect size will be discovered in studies of familial FSGS. For example, Ruf and colleagues18,19 have mapped a recessive gene locus for steroid-responsive FSGS to chromosome 2p with evidence of genetic heterogeneity, and Gbadegesin et al.20 have recently mapped another dominant locus for familial FSGS to the same region. Until recently, the discovery of rare monogenic disease genes remained a tedious task requiring mutation screening gene by gene in linkage regions that may contain many genes. However, this task may be facilitated by the recent availability of massive parallel DNA sequencing (also termed Next Generation sequencing).21 Indeed, the application of whole exome or genome sequencing in combination with a genome-wide linkage scan can provide a powerful approach in disease gene discovery.22,23 Furthermore, genome-wide gene copy number variation represents another complementary approach.24 In parallel, population-based genome-wide association studies are also promising for detecting polygenes with modest effect size, as exemplified by the success of a recent admixture study in identifying a susceptibility/modifier locus for FSGS linked to MYH9/APOL1 in black individuals.25,26 When more pieces of the jigsaw puzzle for FSGS are filled in, this knowledge can provide a strong foundation for future development of comprehensive molecular diagnostic testing and mechanism-based therapeutics. Meanwhile, molecular diagnostics for FSGS can be readily adapted for testing individuals who are at risk for familial FSGS when a specific disease-causing mutation is known. This information may also provide useful guidance to the clinician in deciding whether a course of immunosuppressive drug treatment is appropriate. Otherwise, clinical molecular diagnostics for FSGS should be used with extreme care especially for sporadic cases and only in instances in which there is no ambiguity in interpreting the pathogenicity of the putative mutations; that is, truncating mutations and highly conserved missense mutations supported by a functional studies. DISCLOSURES None. This work is supported by a grant from the Kidney Foundation of Canada to Y.P.