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 Q), (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'.

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease

“…Human genetic studies in the past 2 decades have illuminated podocyte dysfunction as the major contributor to GFB failure in primary NS. Mutations in more than 30 podocyte genes including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4, INF2, and COL4A have been implicated as causal factors for primary podocytopathy and GBM nephropathy (34). With the recent advent of next-generation sequencing, a large number of rare (minor allele frequency < 0.5%) missense variants of unknown significance in both known and novel NS-causing podocyte genes are rapidly emerging in thousands of affected patients (35,36).…”

Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome

“…It remains one of the most intractable kidney diseases (3). The identification of single-gene causes of SRNS and subsequent research on the function of those genes have helped to assemble the essential components of glomerular podocyte function (4)(5)(6). SRNS is genetically heterogeneous, and more than 50 monogenic genes have been discovered to cause podocyte dysfunction if mutated.…”

“…SRNS is genetically heterogeneous, and more than 50 monogenic genes have been discovered to cause podocyte dysfunction if mutated. These findings revealed podocytes as the critical site of pathogenesis in SRNS (5). Fascinatingly, the proteins encoded by the genes that are mutated in monogenic causes of disease have started to coalesce to protein interaction complexes that, through their loss of function, define the pathomechanisms of nephrotic syndrome (5).…”

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

“…We recently demonstrated in a worldwide cohort of 1,783 families that a monogenic cause of SRNS can be detected in 1 of 27 genes in approximately 30% of SRNS cases manifesting before age 25 years (5). Currently, more than 40 monogenic forms of SRNS have been identified (6).…”

“…To date, mutations have been identified in transcription factors and nuclear proteins (WT1, LMX1B, SMARCAL1, NXF5, NUP93, NUP205, and XPO5), lysosomal proteins (SCARB2), basement membrane proteins (LAMB2), and proteins involved in COQ 10 biosynthesis (COQ2, COQ6, PDSS2, and ADCK4) (6). Because genetic mapping data indicated a multitude of potential additional loci for SRNS, we here performed whole exome sequencing (WES) to identify additional monogenic SRNS genes and identified 9 different mutations in sphingosine-1-phosphate lyase (SGPL1) in 7 families as causing a previously unrecognized syndromic SRNS with a combination of ichthyosis/acanthosis, adrenal insufficiency, immunodeficiency, and/or neuronal dysfunction.…”