GENETIC BASIS OF CORTICOSTEROID RESPONSE IN CHILDHOOD NEPHROTIC SYNDROME

点击翻译按钮获取中文摘要

Nephrotic syndrome (NS) is an orphan kidney disease in children. The mechanisms by which corticosteroids induce remission in some patients with NS is not known, nor is the molecular basis of variable response to corticosteroid therapy. In our efforts to understand the molecular basis of corticosteroid response in steroid sensitive nephrotic syndrome (SSNS), we have established a biorepository of more than 1,000 children with SSNS and frequent relapsing/steroid dependent (FR/SD) and non-FR/SD course. We carried out whole genome sequencing in a subset of this cohort with familial disease and identified a segregating rare pathogenic variant H310Y in the gene CLVS1 encoding for clavesin1 as a new cause of SSNS. Clavesin1 is expressed in podocytes and is required for the normal morphology of late endosomes. In preliminary data, we have shown that knockdown of CLVS1 increases apoptosis in human podocyte cell lines. The increased podocyte apoptosis can be rescued by corticosteroid treatment, mimicking the steroid- responsiveness observed in the family with SSNS due to H310Y variant. The proposed study will use a large SSNS patient cohort to determine the prevalence of rare variants in CLVS1 and other podocyte genes previously associated with SSNS, and determine the mechanisms by which pathogenic CLVS1 variants will cause NS phenotypes that are amenable to corticosteroid treatment. Our overarching hypothesis is that rare variants in CLVS1 and other podocyte related genes associated with SSNS are more common in patients with FR/SD SSNS compared to non- FR/SD SSNS, and that the CLVS1 H310Y variant induces an SSNS phenotype by loss of clathrin dependent endocytosis that can be rescued by a corticosteroid-induced increase in clathrin independent endocytosis. We will test our hypothesis through the following aims: 1) Using a large SSNS patient cohort, we will identify rare variants in CLVS1 and other podocyte genes previously associated with SSNS and define genotype-phenotype correlation, 2) Determine the mechanisms by which defects in CLVS1 will cause NS and the molecular basis for corticosteroid response. Data generated from the proposed study will for the first time, provide insight into how podocyte genes can cause NS that is amenable to therapy with corticosteroids and identify new druggable targets for NS.