Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin

• Published in: The Journal of clinical investigation 2006-05, Vol.116 (5), p.1337-1345
• Main Authors: Huber, Tobias B, Kwoh, Christopher, Wu, Hui, Asanuma, Katsuhiko, Gödel, Markus, Hartleben, Björn, Blumer, Ken J, Miner, Jeffrey H, Mundel, Peter, Shaw, Andrey S
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Biomedical research; Causes of; Cell Line; Congenital diseases; Cytoskeletal Proteins; Disease Models, Animal; Etiology; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic research; Glomerulosclerosis, Focal Segmental - genetics; Glomerulosclerosis, Focal Segmental - pathology; Heterozygote; Humans; Kidney diseases; Kidney Failure, Chronic - genetics; Kinases; Medical research; Medicine, Experimental; Mice; Mice, Transgenic; Microfilament Proteins - metabolism; Mutation; Pathogenesis; Proteins; Proteins - metabolism; Proto-Oncogene Proteins c-fyn - metabolism
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci27400

Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular diagnosis resulting in end-stage renal disease. Defects in several podocyte proteins have been implicated in the etiology of FSGS, including podocin, alpha-actinin-4, CD2-associated protein (CD2AP), and TRPC6. Despite our growing understanding of genes involved in the pathogenesis of focal segmental sclerosis, the vast majority of patients with this disease, even those with a familial linkage, lack a clear genetic diagnosis. Here, we tested whether combinations of genetic heterozygosity (bigenic heterozygosity) that alone do not result in clinical kidney disease could function together to enhance susceptibility to glomerular damage and FSGS. Combinations of Cd2ap heterozygosity and heterozygosity of either synaptopodin (Synpo) or Fyn proto-oncogene (Fyn) but not kin of IRRE like 1 (Neph1) resulted in spontaneous proteinuria and in FSGS-like glomerular damage. These genetic interactions were also reflected at a functional level, as we found that CD2AP associates with Fyn and Synpo but not with Neph1. This demonstrates that bigenic heterozygosity can lead to FSGS and suggests that combined mutations in 2 or multiple podocyte genes may be a common etiology for glomerular disease.