Genetics of hereditary nephrotic syndrome: a clinical review

Abstract

Advances in podocytology and genetic techniques have expanded our understanding of the pathogenesis of hereditary steroid-resistant nephrotic syndrome (SRNS). In the past 20 years, over 45 genetic mutations have been identified in patients with hereditary SRNS. Genetic mutations on structural and functional molecules in podocytes can lead to serious injury in the podocytes themselves and in adjacent structures, causing sclerotic lesions such as focal segmental glomerulosclerosis or diffuse mesangial sclerosis. This paper provides an update on the current knowledge of podocyte genes involved in the development of hereditary nephrotic syndrome and, thereby, reviews genotype-phenotype correlations to propose an approach for appropriate mutational screening based on clinical aspects.

Optimized nonviral gene delivery for primary urinary renal progenitor cells to enhance cell migration

“…Genetic manipulation of RPCs ex vivo may present an in key podocyte ultrastructure and attachment proteins such as nephrin, podocin, and laminin β2 lead to podocyte dysfunction (Lovric, Ashraf, Tan, & Hildebrandt, 2016) and kidney failure. These patients often fail to respond to frontline steroid therapy, and 50% develop end-stage kidney failure within 15 years (Ha, 2017). While autologous transfer of uRPCs may present an attractive strategy to restore podocyte number, the same genetic mutations would prevent differentiation into functional podocytes.…”

The status quo and challenges of genetic diagnosis in children with steroid-resistant nephrotic syndrome

“…Later on, a number of disease-causing genes have been discovered. To date, about 53 genes are known to cause SRNS and/or FSGS with all types of modes of inheritance [8]. According to its symptoms, SRNS can be isolated or syndromic, and the following 28 genes are known to cause isolated nephrotic syndrome [3,8,12,13] : ADCK4, ARHGDIA, CD2AP, CFH, COQ2, COQ6, CUBN, DGKE, ITGA3, ITGB4, LAMB2, MEFV, MYO1E, NPHS1, NPHS2, PDSS2, PLCE1, PTPRO, SCARB2, SMARCAL1, TTC21B, ACTN4, ARHGAP24, INF2, LMX1B, PAX2, TRPC6, and WT1.…”

“…Recent discoveries of genes encoding proteins crucial for the establishment and maintenance of glomerular filtration barrier have revealed the importance of glomerular epithelial cells (podocytes) in the pathogenesis of SRNS [7]. The most common histology of SRNS is focal segmental glomerular sclerosis (FSGS) [8]. About 11-50% of patients with FSGS are at risk of recurrence after kidney transplantation and eventually progress to terminal renal failure [8,9], but the risk for recurrence is lower in FSGS patients with monogenic (single gene) forms of SRNS than those with nonhereditary forms [10].…”

“…The most common histology of SRNS is focal segmental glomerular sclerosis (FSGS) [8]. About 11-50% of patients with FSGS are at risk of recurrence after kidney transplantation and eventually progress to terminal renal failure [8,9], but the risk for recurrence is lower in FSGS patients with monogenic (single gene) forms of SRNS than those with nonhereditary forms [10]. One of the new factors that may predict response to therapy and renal outcomes is genetic variants of nephrotic syndrome [4].…”

Nucleoporin 133 deficiency leads to glomerular damage in zebrafish

“…Although nonhereditary forms of SRNS seem to be prevalent, studies over the last years have identified over 50 dominant or recessive single-gene mutations in a significant percentage (30%) of patients with early-onset SRNS and FSGS (reviewed or discussed in 6,[8][9][10][11] ). While some of these genes have podocyte-specific or -restricted functions, these studies also unveiled the implication of multiple cellular processes in the establishment or maintenance of the glomerular filtration barrier 7,12,13 . In particular, these genetic studies have identified mutations in Nup93 and Nup205, two constituents of the inner ring of the NPC 14 and in Nup107, a constituent of the Y-complex (Nup107/160-complex) that builds up the cytoplasmic and nuclear rings of the NPC 15,16,17 .…”