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Child Kidney Dis > Volume 23(2); 2019 > Article
Park: Genetic Basis of Steroid Resistant Nephrotic Syndrome

Abstract

Steroid-resistant nephrotic syndrome (SRNS) has long been a challenge for clinicians due to its poor responsiveness to immunosuppressants, and rapid progression to end-stage renal disease. Identifying a monogenic cause for SRNS may lead to a better understanding of podocyte structure and function in the glomerular filtration barrier. This review focuses on genes associated with slit diaphragm, actin cytoskeleton, transcription factors, nucleus, glomerular basement membrane, mitochondria, and other proteins that affect podocyte biology.

Introduction

Nephrotic syndrome (NS) in children refers to a glomerular filtration barrier (GFB) failure disease. NS manifests itself with severe proteinuria, and later on leads to hypoalbuminemia, hypercholesterolemia, and generalized edema [1]. NS has long been considered an immunological derangement since most patients respond well to immune suppression and some patients recur even after renal transplantation. However, the non-responsiveness of 15–20% of NS patients to conventional immunosuppressants remained unexplained [2].
Steroid-resistant nephrotic syndrome (SRNS) is defined as failure to achieve remission after eight weeks of daily corticosteroid therapy. SRNS is the second most frequent cause of end-stage renal disease (ESRD) in childhood, and mostly associated with focal segmental glomerulosclerosis (FSGS) [3]. SRNS is a genetically heterogeneous disease with over 70 SRNS- and/or FSGS-causing genes [3,4]. A single causative genetic mutation in 20-30% of SRNS cohort patients was identified in recent studies [5-7]. Identification of a genetic cause of SRNS implied podocyte as a central player in proteinuria pathogenesis, and advanced our understanding of the podocyte pathobiology.
Podocytes are a major GFB component, and are considered to be highly specialized and terminally-differentiated with limited regenerative capacity. Podocyte injury leads to foot process effacement, and is associated with urinary protein leakage, renal function deterioration, and progression to ESRD [8]. Protein-coding genes that affect podocyte structural stability and function can be categorized as, (1) slit diaphragm (SD)-associated, (2) actin cytoskeleton and membrane protein-encoding, (3) transcription factor and nuclear protein-encoding, (4) glomerular basement membrane (GBM), (5) mitochondrial, and (6) lysosomal, metabolic, and cytosolic protein-encoding genes (Table 1).
Herein, several SRNS-associated genes are reviewed with respect to their roles in podocyte pathobiology.

Slit diaphragm-associated genes

The SD is a unique intercellular junction that connects neighboring podocyte foot processes, regulates filtration selectivity and mediates a variety of signaling pathways related to the plasticity of foot processes [9]. The genetic basis of SRNS was first established by findings on SD proteins nephrin and podocin, which are encoded by NPHS1 and NPHS2 , respectively.
Nephrin is a large transmembrane protein within the zipper-like SD structure. Podocin is an integral membrane protein, and acts as a binder between nephrin and podocyte actin cytoskeleton. Mutations in genes encoding these proteins were found to be associated with autosomal recessive (AR) nephrotic syndrome presenting early in life [10,11]. At least 250 and 170 mutations in NPHS1 and NPHS2 were found to cause early-onset nephrotic syndrome, respectively. Phospholipase C epsilon 1 (encoded by PLCE1) is expressed in the developing kidney, and affects cell adhesion by interacting with podocyte cell junction proteins. Mutations in PLCE1 were found to cause early-onset SRNS via AR inheritance [12]. Transient receptor potential channel 6 (encoded by TRPC6 ) binds to podocin, and regulates the calcium influx into the podocytes. TRPC6 mutations were found to cause dysregulation of the actin cytoskeleton, and result in podocyte injury, with an autosomal dominant (AD) inheritance and usually onset later in childhood [13]. CD2AP is an adaptor protein linking nephrin and podocin to the podocyte actin cytoskeleton. The CD2AP protein is involved in actin remodeling via synaptopodin binding. Mutations in the gene encoding CD2AP were found to cause AD and AR nephrotic syndrome [14].

Actin cytoskeleton and membrane proteinencoding genes

After the breakthrough discovery of SD genes, additional genes related to proteins of foot process actin cytoskeleton were revealed. Podocyte foot process is a highly dynamic architecture including parallel actin filament bundles, connecting adjacent foot processes to each other, and forming the SD. Mutations in podocyte cytoskeleton-associated genes were found to alter podocyte actin dynamics, and cause changes in podocyte morphology and function [12].
α-actinin 4 (encoded by ATCN4 ) is an F-actin-binding protein that regulates the binding affinity of actin and adhesion to the GBM. ATCN4 mutations were found to be associated with AD late-onset SRNS [16]. Non-muscle myosin heavy chain 9 (encoded by MYH9) is a myosin IIA subunit that is involved in actin cytoskeleton translocation in the podocytes. MYH9 mutations were found to cause the syndromic form of SRNS called MYH9 -related disease, with symptoms of AD FSGS, macrothrombocytopenia, and sensorineural deafness [17]. Inverted formin-2 (encoded by INF2 ) also regulates actin-binding to the podocytes. INF2 mutations were found to be associated with adolescent-onset AD FSGS and Charcot-Marie-Tooth disease [18].
Rho GTPase (also known as RHoA, Rac, or Cdc42) maintains the integrity of podocyte structure by regulating the actin bundle and actin network formation. Mutations in ARHGAP24 (encoding Rho GTPase activating protein 24) were demonstrated to increase the Rho GTPase activity in podocytes, thereby leading to AD-FSGS [19]. ARHGDIA and KANK1/KANK2/KANK4 mutations were also found to increase Rho GTPase activity in podocytes, and were associated with AR-FSGS [20,21].

Transcription factor and nuclear proteinencoding genes

Wilms’ tumor protein 1 (encoded by WT1) is a transcription factor with a critical role in renal development and podocyte stabilization. WT1 gene mutations encompass a wide range of sequence variations, and exhibit a variety of phenotypes from isolated proteinuria to Fraiser- and Denys-Drash syndromes [22,23]. Along with NPHS1, NPHS2 , and LAMB2, WT1 is one of the most common genes found in congenital and infantile nephrotic syndrome [24]. Paired box protein 2 (encoded by PAX2 ) is also an important transcription factor during nephrogenesis. PAX2 variants were detected within a wide phenotypic spectrum, from congenital anomaly of kidney and urinary tract to late-onset FSGS [25]. LIM homeobox transcription factor 1β (encoded by LMX1B) protein regulates the development of podocyte foot process and SD. LMX1B mutations were found to exhibit clinical manifestations ranging from isolated proteinuria to Nail-Patella syndrome [26].
Nuclear pore complex proteins are involved in another pathway implicated in SRNS pathogenesis. This was determined through the identification of mutations in six genes (NUP85, NUP93, NUP107, NUP133, NUP160, NUP205 ). Mutations in these nuclear pore complex protein genes lead to abnormal nucleoprotein assembly, thereby inhibiting podocyte proliferation, promoting podocyte apoptosis, and disrupting the structural integrity of the GFB. Mutations in these genes were mostly found to underlie childhoodonset AR-FSGS [27-29].

Glomerular basement membrane genes

The GBM is composed of a network of laminin, type IV collagen, nidogen, and heparan sulfate proteoglycans. GBM is a GFB component located between podocytes and endothelial cells. Changes in GBM composition or morphology are known to affect the integrity of glomerular filtration [30].
Laminin is a heterotrimer of α, β, and γ glycoprotein chains. Mutations in LAMB2 (encoding laminin β2) were found to cause isolated congenital and childhood-onset SRNS or typically Pierson syndrome, depending on the genotype [31]. The α3, α4, and α5 collagen IV heterotrimers are essential for maintaining the GBM. Defects in these proteins impair podocyte adherence to GBM, and accelerate podocyte detachment. Mutations in type IV collagen α3, α4, and α5 chains (encoded by COL4A3, CLO4A4 , and COL4A5 ) were found to cause Alport syndrome, which is characterized by familial nephropathy with sensorineural deafness and ocular abnormalities [32].

Mitochondrial genes

The discovery of mitochondrial gene mutations raised awareness regarding the importance of mitochondrial podocytopathy in SRNS. Coenzyme Q10, also known as ubiquinone, is essential for transporting electrons in the mitochondrial respiratory chain to produce energy. Genetic defects in coenzyme Q10 biosynthesis lead to mitochondrial dysfunction, thereby resulting in podocyte injury and apoptosis.
Mutations in four genes (COQ2, COQ6, COQ8B/ADCK4, PDSS2) hitherto associated with coenzyme Q10 biosynthesis have been identified to cause SRNS. The mutations in COQ6 and COQ8B/ADCK4 were found to be associated with early-onset SRNS and sensorineural deafness, and childhood-onset SRNS with nephrocalcinosis, respectively [33-36]. In some rare cases, the A3243G mutation in the MTTL1 gene (encoding leucine tRNA) caused a respiratory chain defect, and was associated with FSGS and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome [37].

Lysosomal, metabolic, and cytosolic proteinencoding genes

Various pathways related to lysosomes, endosomes, and metabolism are associated with SRNS development. Mutations in SCARB2 (encoding a lysosomal integral membrane protein) were found to cause podocyte damage via impaired autophagy regulation, thereby resulting in myoclonus renal failure syndrome [38]. A mutation in TTC21B (encoding an intraflagellar transport-A component of primary cilium) was found to be associated with AR FSGS and nephronophthisis [39]. Diacylglycerol kinase ε (encoded by DGKE ) is an intracellular lipid kinase. Diacyclglycerol kinase ε regulates the phosphatidylinositol cycle by controlling the concentration of diacylglycerol. A DGKE mutation was found to be associated with AR NS and atypical hemolytic uremic syndrome [40].
Other SRNS-associated genes not mentioned above are presented in Table 1.

Conclusions

The identification of genetic mutations in SRNS expanded our knowledge of the molecular basis of proteinuria, and took us a step closer towards finding a cure. However, clinical heterogeneity is observed in patients carrying identical mutation, and these genes are only responsible for a small part of the SRNS pathogenesis; a large portion remains unknown. Further research is needed to identify other pathogenic mutations and to clarify currently unknown mechanisms of SRNS pathogenesis in order to provide a personalized therapeutic approach, including avoidance of unnecessary immunosuppressive therapy, screening for associated extra-renal malformations, prediction of posttransplant outcome, and genetic counselling.

Notes

Conflict of interest
The author declares no competing interests.

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Table 1.
Genes Associated with Steroid-resistant Nephrotic Syndrome
Gene Protein Mode of inheritance Reference
Slit diaphragm-associated genes
NPHS1 Nephrin AR (10)
NPHS2 Podocin AR (11)
PLCE1 Phospholipase C epsilon 1 AR (12)
TRPC6 Transient receptor potential channel C6 AD (13)
CD2AP CD2-associated protein AD, AR (14)
CRB2 Crumbs family member2 AR (41)
FAT1 FAT atypical cadherin 1 AR (42)
KIRREL1 Kin of IRRE-like protein 1 AR (43)
Actin cytoskeleton and membrane encoding genes
ACTN4 α-actinin 4 AD (16)
MYH9 Myosin heavy chain 9, non-muscle AD (17)
INF2 Inverted formin 2 AD (18)
MYO1E Myosin 1E AR (44)
MAGI2 Membrane Associated Guanylate Kinase, inverted 2 AR (45)
ANLN Anillin actin binding protein AD (46)
ARHGA24 Rho GTPase-activating protein 24 AD (19)
ARHGDIA Rho GDP dissociation inhibitor α AR (20)
KANK 1/2/4 Kidney ankyrin repeat-containing protein AR (21)
SYNPO Synaptopodin AD (47)
PTPRO Protein-tyrosine phosphatase- RO AR (48)
EMP2 Epithelial membrane protein 2 AR (49)
APOL1 Apolipoprotein L1 Biallelic (50)
CUBN Cubilin AR (51)
PODXL Podocalyxin AD (52)
DLC1 DLC1 Rho GTPase-activating protein AR (53)
ITSN 1/2 Intersectin protein AR (53)
TNS2 Tensin-2 AR (53)
Transcription factor and nucleus encoding genes
WT1 Wilms’ tumor protein 1 AD, AR (22, 23)
PAX2 Paired box protein 2 AD (25)
LMX1B LIM homeobox transcription factor 1β AD (26)
SMARCAL1 SMARCA-like protein AR (54)
NUP 85/93/107/133/160/205 Nuclear pore complex protein AR (27-29)
XPO5 Exportin 5 AR (29)
E2F3 E2F transcription factor AD (55)
NXF5 Nuclear RNA export Factor 5 XLR (56)
MAFB MAF bZIP transcription factor B AD (57)
LMNA Lamin A and C AD (58)
WDR73 WD repeat domain 73 AR (59)
OSGEP KEOPS complex protein AR (60)
TP53RK KEOPS complex protein AR (60)
TPRKB KEOPS complex protein AR (60)
LAGE3 KEOPS complex protein XL (60)
Glomerular basement membrane genes
LAMB2 Laminin subunit β2 AR (31)
ITGB4 Integrin β4 AR (61)
ITGA3 Integrin α3 AR (62)
COL4A 3/4/5 Type IV collagen α3, α4, α5 AD, AR, XL (32)
GPC5 Glypican 5 Risk gene (63)
CD151 CD151 antigen AR (64)
Mitochondrial genes
COQ2 Coenzyme Q2 AR (33)
COQ6 Coenzyme Q6 AR (34)
PDSS2 Prenyl-diphosphate synthase subunit 2 AR (35)
COQ8B/ADCK4 Coenzyme Q8B AR (36)
MTTL1 Mitochondrial tRNA 1 Mt (37)
Lysosomal, metabolic, and cytosolic protein encoding genes
SCARB2 Scavenger receptor class B, member 2 AR (38)
OCRL1 Oculocerebrorenal syndrome of Lowe XLR (65)
ZMPSTE24 Zinc metallopeptidase STE24 AR (66)
PMM2 Phosphomannomutase 2 AR (67)
ALG1 Asparagine-linked glycosylation 1 AR (68)
TTC21B Tetratricopeptide repeat protein 21B AR (39)
CFH Complement factor H AR (69)
DGKE Diacylglycerol kinase ε AR (40)
CDK20 Cyclin-dependent kinase AR (53)
MEFV Pyrin AR (70)
NEIL1 Nei endonuclease VIII-like 1 AR (71)
GAPVD1 GTPase activating protein and VPS9 domains 1 AR (72)
ANKFY1 Ankyrin repeat and FYVE domain containing 1 AR (72)
TBC1D8B TBC1 domain family member 8B XL (73)

AD, Autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive; XL, X-linked; Mt, Mitochondrial

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