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

Lookup NU author(s): Professor John Sayer

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Abstract

The autosomal recessive kidney disease nephronophthisis (NPHP) consdtutes 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 X-PNPEP3 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.


Publication metadata

Author(s): O'Toole JF, Liu YJ, Davis EE, Westlake CJ, Attanasio M, Otto EA, Seelow D, Nurnberg G, Becker C, Nuutinen M, Karppa M, Ignatius J, Uusimaa J, Pakanen S, Jaakkola E, van den Heuvel LP, Fehrenbach H, Wiggins R, Goyal M, Zhou WB, Wolf MTF, Wise E, Helou J, Allen SJ, Murga-Zamalloa CA, Ashraf S, Chaki M, Heeringa S, Chernin G, Hoskins BE, Chaib H, Gleeson J, Kusakabe T, Suzuki T, Isaac RE, Quarmby LM, Tennant B, Fujioka H, Tuominen H, Hassinen I, Lohi H, van Houten JL, Rotig A, Sayer JA, Rolinski B, Freisinger P, Madhavan SM, Herzer M, Madignier F, Prokisch H, Nurnberg P, Jackson P, Khanna H, Katsanis N, Hildebrandt F

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2010

Volume: 120

Issue: 3

Pages: 791-802

Print publication date: 01/03/2010

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation

URL: http://dx.doi.org/10.1172/JCI40076

DOI: 10.1172/JCI40076


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