Translating genetic findings in hereditary nephrotic syndrome: the missing loops

Abstract

Nephrotic syndrome (NS) is a clinicopathological entity characterized by proteinuria, hypoalbuminemia, peripheral edema, and hyperlipidemia. It is the most common cause of glomerular disease in children and adults. Although the molecular pathogenesis of NS is not completely understood, data from the study of familial NS suggest that it is a "podocytopathy." Virtually all of the genes mutated in hereditary NS localize to the podocyte or its secreted products and the slit diaphragm. Since the completion of human genome sequence and the advent of next generation sequencing, at least 29 causes of single-gene NS have been identified. However, these findings have not been matched by therapeutic advances owing to suboptimal in vitro and in vivo models for the study of human glomerular disease and podocyte injury phenotypes. Multidisciplinary collaboration between clinicians, geneticists, cell biologists, and molecular physiologists has the potential to overcome this barrier and thereby speed up the translation of genetic findings into improved patient care.

A Review of Podocyte Biology

“…Podocyte depletion can also occur and has been found to correlate with the development of glomerular sclerosis and chronic kidney disease [9]. Since the identification of the NPHS1 gene for the first specialized nephrotic protein, nephrin, approximately 40 genes have been implicated in the development of FSGS and related nephrotic diseases [10,11]. Most can be divided into 2 groups: those that are associated with actin dynamics and largely affect the structural integrity of the foot processes, and those that are related to adhesion to the GBM and may contribute to the loss of podocyte density as podocytes detach.…”

Urinary Anomalies in 22q11.2 Deletion (DiGeorge syndrome): From Copy Number Variations to Single-Gene Determinants of Phenotype

“…More recently, these modalities have been combined with whole-exome sequencing and other next-generation sequencing strategies to accelerate the pace of gene discovery. 18 This approach was used in the identification of CAKUT genes such as ROBO2 , DSTYK , and TNXB . 9,19,20 However, the method is very challenging because of phenotypic heterogeneity of CAKUT.…”

Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population

“…The precise molecular pathophysiology of SRNS remains unclear, but it is understood to be caused by podocyte dysfunction or loss, leading to dysfunction of the charge- and size-selective glomerular filtration barrier ( 3 , 12 ). The glomerular filtration barrier consists of three layers- a fenestrated capillary endothelium, the glomerular basement membrane, and podocytes with interdigitating foot processes connected by a slit diaphragm.…”