O97
IQCJ podocytopathy associated with primary renal failure and de novo
membranous nephropathy post transplantation.
Rachel Lennon1, Edward A McKenzie1, Patrick Caswell1, T Burgis1, Jill Urquhart2,
Sarah Daly2, Helen Stuart2, Jill Clayton- Smith2, Graeme Black2, Shelley Harris3,
Judith Worthington3, Muir Morton3, Colin D Short3, Laurie Solomon4, Martin
Chanayireh5, Catherine Keeling6, Lorna McWilliam6, Ian S Roberts7, Ron Korstanje8,
Nils Hanke9,10, Herman Haller9,10, Mario Schiffer9,10, Paul E Brenchley3,11.
1
Wellcome Trust Centre for Cell-Matrix Research, University of Manchester
Manchester Centre for Genomic Medicine, Manchester 3Manchester Institute of
Nephrology & Transplantation, Manchester4 Renal Unit, Lancashire Teaching
Hospitals, Preston 5Renal Unit, Hull Royal Infirmary 6Department of Lab Medicine,
CMFT, Manchester 7Department of Cellular Pathology, John Radcliffe Infirmary, Oxford
8
Jackson Laboratories, Bar Harbor, Maine, USA 9Department of Nephrology, Hannover
Medical School, Hannover, Germany 10Mount Desert Island Biological Laboratories,
Salsbury Cove, Maine, USA 11Institute of Cardiovascular Sciences, University of
Manchester
2
Introduction. The podocyte is an integral component of the glomerular filtration barrier
and mutations in podocyte genes account for cases of familiar and sporadic glomerular
disease. Following renal transplantation, some patients develop autoimmune
glomerular disease with antibodies specific to nascent podocyte antigens, a process
which can limit graft survival.
Methods. We investigated two siblings with primary glomerular disease and posttransplant membranous nephropathy using autozygosity mapping, copy number
analysis by microarray, whole exome sequencing and post-transplant antibody
screening. Immunohistochemical and electron microscopy studies were performed on
native and transplant kidney biopsy samples. The functional effects of the affected
gene were studied in zebrafish and human podocytes.
Results. 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.
Post 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.
Conclusions. We describe a new podocytopathy based on a genomic deletion on
Chromosome 3 close to IQCJ, which leads to primary renal failure. Following renal
transplantation, possession of the homozygous IQCJ deletion causes de novo
membranous nephropathy in the allograft within 12 months with rapid graft loss within
two years. Dysregulated IQCJ may play a role in primary glomerular disease and
become a target antigen in MN.