Nephronophthisis (NPHP) is the most common genetic cause of kidney failure in children. Ten causative genes (NPHP1-NPHP9 and NPHP11), all of which generate proteins that localize to a cellular complex known as the primary cilia-centrosome complex, have been identified previously.
A team of researchers, at the University of Michigan Health System, Ann Arbor, and Duke University Medical Center, Durham, has now identified an association between mutations in the XPNPEP3 gene and an NPHP-like nephropathy in two consanguineous families, one in northern Finland and one in Turkey.
Unlike all the known NPHP proteins, XPNPEP3 protein localizes to cellular compartments known as mitochondria. However, in vivo analysis in zebrafish indicated that XPNPEP3 protein has a role in ciliary function, as it degraded several ciliary cystogenic proteins.
The authors therefore conclude that there is a link between mitochondria and ciliary dysfunction, a key component of NPHP. As highlighted by Erwin Böttinger, at Mount Sinai School of Medicine, New York, these data provide exciting new avenues of research for understanding ciliopathies, genetic disorders caused by damage to cellular structures known as primary cilia.
The research appears in the Journal of Clinical Investigation.
- O'Toole et al. Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. Journal of Clinical Investigation, 2010; DOI: 10.1172/JCI40076
- Erwin P. Böttinger. Lights on for aminopeptidases in cystic kidney disease. Journal of Clinical Investigation, 2010; DOI: 10.1172/JCI42378
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