Exploring the genetic basis of early-onset chronic kidney disease

Abstract

The primary causes of chronic kidney disease (CKD) in children differ from those of CKD in adults. In the USA the most common diagnostic groups of renal disease that manifest before the age of 25 years are congenital anomalies of the kidneys and urinary tract, steroid-resistant nephrotic syndrome, chronic glomerulonephritis and renal cystic ciliopathies, which together encompass >70% of early-onset CKD diagnoses. Findings from the past decade suggest that early-onset CKD is caused by mutations in any one of over 200 different monogenic genes. Developments in high-throughput sequencing in the past few years has rendered identification of causative mutations in this high number of genes feasible. Use of genetic analyses in patients with early onset-CKD will provide patients and their families with a molecular genetic diagnosis, generate new insights into disease mechanisms, facilitate aetiology-based classifications of patient cohorts for clinical studies, and might have consequences for personalized approaches to the prevention and treatment of CKD. In this Review, we discuss the implications of next-generation sequencing in clinical genetic diagnostics and the discovery of novel genes in early-onset CKD. We also delineate the resulting opportunities for deciphering disease mechanisms and the therapeutic implications of these findings.

Figure 1

Percentage of genetic findings in SRNS families. We previously obtained samples from 1,783 SRNS families worldwide and detected the disease-causing mutation in 526 families (29.5%). For 8 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 (45.2%, 66/146), Turkey (37.3%, 62/169), Germany (26.9%, 123/457), Switzerland (22.1 %, 21/94), India (19.7%, 25/127,), Ann Arbor (14.3%, 8/56), 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)

Figure 2. Proteins involved in single-gene causes and pathogenic pathways of steroid resistant nephrotic syndrome

Identification of single-gene (monogenic) causes of steroid resistant nephrotic syndrome 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, that attach to the glomerular basement membrane (GBM) via laminin-integrin receptors. Proteins that if mutated cause recessive monogenic forms of SRNS in red, and proteins that if mutated cause dominant forms of SRNS 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 adhessions), 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 biosynthesis. IQGAP, IQ motif containing GTPase activating protein 1; P, Paxillin; V, Vinculin and T, Talin. 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; FAT1, FAT tumor suppressor homolog 1; GBM, glomerular basement membrane. ITGA3, integrin, alpha 3; ITGB4, integrin, beta 4; KANK, KN otif 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 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.