Genetic testing in steroid-resistant nephrotic syndrome: when and how?

Abstract

Steroid-resistant nephrotic syndrome (SRNS) represents the second most frequent cause of chronic kidney disease in the first three decades of life. It manifests histologically as focal segmental glomerulosclerosis (FSGS) and carries a 33% risk of relapse in a renal transplant. No efficient treatment exists. Identification of single-gene (monogenic) causes of SRNS has moved the glomerular epithelial cell (podocyte) to the center of its pathogenesis. Recently, mutations in >30 recessive or dominant genes were identified as causing monogenic forms of SRNS, thereby revealing the encoded proteins as essential for glomerular function. These findings helped define protein interaction complexes and functional pathways that could be targeted for treatment of SRNS. Very recently, it was discovered that in the surprisingly high fraction of ∼30% of all individuals who manifest with SRNS before 25 years of age, a causative mutation can be detected in one of the ∼30 different SRNS-causing genes. These findings revealed that SRNS and FSGS are not single disease entities but rather are part of a spectrum of distinct diseases with an identifiable genetic etiology. Mutation analysis should be offered to all individuals who manifest with SRNS before the age of 25 years, because (i) it will provide the patient and families with an unequivocal cause-based diagnosis, (ii) it may uncover a form of SRNS that is amenable to treatment (e.g. coenzyme Q₁₀), (iii) it may allow avoidance of a renal biopsy procedure, (iv) it will further unravel the puzzle of pathogenic pathways of SRNS and (v) it will permit personalized treatment options for SRNS, based on genetic causation in way of 'precision medicine'.

Keywords: clinical genetic testing; molecular genetics; monogenic disease; pathogenesis of nephrotic syndrome; steroid-resistant nephrotic syndrome (SRNS).

FIGURE 1:

Proteins involved in single-gene causes and pathogenic pathways of SRNS. Identification of single-gene (monogenic) causes of SRNS has revealed the renal glomerular epithelial cell, the podocyte, as the center of action in the pathogenesis of SRNS, because all of the related genes are highly expressed in podocytes. In this way, identification of genes that, if mutated, cause SRNS revealed certain proteins and functional pathways as essential for glomerular function, because a mutation in any single one of them is sufficient to cause SRNS. This figure depicts a simplified cross-section through two neighboring podocyte foot processes, which attach to the GBM via laminin/integrin receptors. Proteins that if mutated cause recessive monogenic forms of SRNS are in red, and proteins that if mutated cause dominant forms of SRNS are in blue. These SRNS-related proteins were found to be part of protein–protein interaction complexes that participate in defined structural components or signaling pathways of podocyte function (black frames). These proteins include: laminin/integrin receptors (focal adhesions), actin-binding proteins, glomerular slit membrane-associated components, actin-regulating small GTPases of the Rho/Rac/Cdc42 family, lyposomal proteins, nuclear transcription factors and proteins involved in coenzyme Q₁₀(C_oQ₁₀) biosynthesis. Proteins that are encoded by recessive SRNS genes are marked in red: ADCK4, AarF domain containing kinase 4; ARHGDIA, Rho GDP dissociation inhibitor (GDI) alpha; CD2AP, CD2-associated protein; CFH, Complement factor H; COQ2, coenzyme Q2 4-hydroxybenzoate polyprenyltransferase; COQ6, coenzyme Q6 monooxygenase 6; CRB2, Crumbs family member 2; DGKE, Diacylglycerol kinase, epsilon EMP2, epithelial membrane protein 2; GBM, glomerular basement membrane; ITGA3, integrin, alpha 3; ITGB4, integrin, beta 4; KANK, KN motif And Ankyrin Repeat Domains 1/2/4; LAMB2, laminin, β2; MTTL1, mitochondrial tRNA leucine 1; MYO1E, Homo sapiens myosin 1e; NPHS1, nephrin; NPHS2, podocin; NUP93, Nucleoporin 93 kDa; NUP107, Nucleoporin 107 kDa; NUP205, Nucleoporin 205 kDA; PDSS2, prenyl (decaprenyl) diphosphate synthase, subunit 2; PLCE1, phospholipase C, epsilon 1; PTPRO, protein tyrosine phosphatase, receptor type, O; SCARB2, scavenger receptor class B, member 2; SMARCAL1, SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily a-like 1; WDR73, WD repeat domain 73; XPO5, Exportin 5. Proteins that are encoded by dominant SRNS genes are marked in blue: ACTN4, actinin, alpha 4; ANLN, anillin; ARHGAP24, Rho GTPase-activating protein 24; INF2, inverted formin, FH2 and WH2 domain containing; LMX1B, LIM homeobox transcription factor 1-beta; MYH9, Myosin, heavy chain 9; TRPC6, transient receptor potential cation channel, subfamily C, member 6; WT1, Wilms tumor 1. IQGAP, IQ motif containing GTPase activating protein 1; P, Paxillin; V, Vinculin and T, Talin.

FIGURE 2:

Age of onset distribution (in years) for 1589 of 1783 examined families with SRNS [49]. A total of 1589 individuals from different families manifested with SRNS before 18 years of age. Graph indicates percentage of solved families per year of age of onset. Black dotted line represents a binomial fit of age-related percent of families with causative mutation (in families with more than one affected family member, the mean age of onset from all affected individuals was used).

FIGURE 3:

Percentage of genetic findings in SRNS families from the eight largest contributing centers. We obtained samples from 1783 SRNS families worldwide and detected the disease-causing mutation in 506 families (28.4%). For eight centers, we detected the disease-causing mutations in the following fractions (families in whom we detected the causative mutation/total families examined from this center): Saudi-Arabia (45.2%, 28/62), Egypt (43.8%, 64/146), Turkey (35.5%, 60/169), Germany (25.6%, 117/457), Switzerland (21.3%, 20/94), India (19.7%, 25/127), Ann Arbor (12.5%, 7/56) and Los Angeles (13.7%, 7/51). Inset: the detection rate of the disease-causing mutations strongly correlates with the rate of consanguinity between the different centers (R² = 0.9414) [49].

FIGURE 4:

Response of SRNS to oral coenzyme Q₁₀(C_oQ₁₀) in monogenic SRNS due to a mutation in an enzyme of the coenzyme Q₁₀ biosynthesis pathway. In a 5-year-old girl with SRNS and a causative homozygous mutation in the COQ6 gene, treatment with coenzyme Q₁₀ was commenced during remission. Following inadvertent interruption of coenzyme Q₁₀ administration, proteinuria rose into the nephrotic range. Following reinstitution of therapy, proteinuria normalized [12].