Podocytopathy in primary renal failure and de-novo membranous nephropathy post transplantation

Abstract Background The podocyte is a key component of the glomerular filtration barrier, and mutations in podocyte genes account for familiar and sporadic glomerular disease. After renal transplantation, some patients develop autoimmune glomerular disease with antibodies specific to nascent podocyte antigens, a process that can limit graft survival. We aimed to determine the molecular diagnosis in a family with primary renal failure and de-novo membranous nephropathy post transplantation. Methods We studied two siblings with primary glomerular disease and post-transplant membranous nephropathy using autozygosity mapping, whole exome sequencing, and post-transplant antibody screening. Native and transplant kidney biopsy samples were assessed in immunohistochemical and electron microscopy studies. The functional effects of the affected gene were studied in zebrafish and human podocytes. Findings We identified a novel 129 kb genomic deletion adjacent to exon 1 of IQCJ on chromosome 3 which was homozygous in siblings and heterozygous in their parents. After transplantation, both siblings were seropositive for anti-IQCJ antibodies. Native kidney biopsy tissue identified abnormal podocyte structure and cytoplasmic IQCJ. Transient knockdown of the IQCJ gene in zebrafish caused oedema, consistent with a glomerular phenotype. Human podocytes expressed IQCJ in vesicles resembling autophagosomes. Interpretation We describe a new podocytopathy based on a genomic deletion on chromosome 3 close to IQCJ, which leads to primary renal failure. After renal transplantation, possession of the homozygous IQCJ deletion causes de-novo membranous nephropathy in the allograft within 12 months with rapid graft loss within 2 years. The dysregulation of this gene might have a role in primary glomerular disease or as a target for de-novo membranous nephropathy after transplantation. Funding Wellcome Trust.