Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.

Abstract

The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.

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Citation

Published Version (Please cite this version)

10.1172/JCI40076

Publication Info

O'Toole, JF, Y Liu, EE Davis, CJ Westlake, M Attanasio, EA Otto, D Seelow, G Nurnberg, et al. (2010). Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J Clin Invest, 120(3). pp. 791–802. 10.1172/JCI40076 Retrieved from https://hdl.handle.net/10161/4325.

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Scholars@Duke

Davis

Erica Ellen Davis

Associate Professor of Pediatrics

Two key questions thematically underscore my research in the Center for Human Disease Modeling at Duke University: First of all, how can variation at the DNA level be functionally interpreted beyond the resolution of genetics arguments alone? Secondly, once empowered with functional information about genetic variants, how can pathogenic alleles be mapped back to disease phenotypes? Using the ciliary disease module as a model system of investigation, we are using multidisciplinary tactics to address these questions and continue to harness these approaches toward the further dissection of the architecture of human genetic disease. Moreover, we have applied the in vivo tools and lessons learned from ciliary phenotypes affecting the renal, craniofacial, and central nervous systems to interrogate rare pediatric disorders characterized by these phenotypic hallmarks.


Zhou

Weibin Zhou

Assistant Professor in Medicine

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