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Title: Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy
Authors: O'Toole, John F
Liu, Yangjian
Davis, Erica E
Westlake, Christopher J
Attanasio, Massimo
Otto, Edgar A
Seelow, Dominik
Nurnberg, Gudrun
Becker, Christian
Nuutinen, Matti
Kärppä, Mikko
Ignatius, Jaakko
Uusimaa, Johanna
Pakanen, Salla
Jaakkola, Elisa
van den Heuvel, Lambertus
Fehrenbach, Henry
Wiggins, Roger
Goyal, Meera
Zhou, Weibin
Wolf, Matthias T F
Wise, Eric
Helou, Juliana
Allen, Susan J
Murga-Zamalloa, Carlos A
Ashraf, Shazia
Chaki, Moumita
Heeringa, Saskia
Chernin, Gil
Hoskins, Bethan E
Chaib, Hassan
Gleeson, Joseph
Kusakabe, Takehiro
Suzuki, Takako
Isaac, R Elwyn
Quarmby, Lynne M
Tennant, Bryan
Fujioka, Hisashi
Tuominen, Hannu
Hassinen, Ilmo
Lohi, Hellevi
van Houten, Judith L
Rotig, Agnes
Sayer, John A
Rolinski, Boris
Freisinger, Peter
Madhavan, Sethu M
Herzer, Martina
Madignier, Florence
Prokisch, Holger
Nurnberg, Peter
Jackson, Peter K
Jackson, Peter
Khanna, Hemant
Katsanis, Nicholas
Hildebrandt, Friedhelm # ×
Issue Date: Mar-2010
Publisher: American Society for Clinical Investigation
Series Title: Journal of Clinical Investigation vol:120 issue:3 pages:791-802
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.
URI: 
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

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