Show simple item record O'Toole, JF Liu, Y Davis, EE Westlake, CJ Attanasio, M Otto, EA Seelow, D Nurnberg, G Becker, C Nuutinen, M Kärppä, M Ignatius, J Uusimaa, J Pakanen, S Jaakkola, E van den Heuvel, LP Fehrenbach, H Wiggins, R Goyal, M Zhou, W Wolf, MT 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, PK Khanna, H Katsanis, N Hildebrandt, F
dc.coverage.spatial United States 2011-06-21T17:27:54Z 2010-03
dc.identifier 40076
dc.identifier.citation J Clin Invest, 2010, 120 (3), pp. 791 - 802
dc.description.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.
dc.format.extent 791 - 802
dc.language ENG
dc.language.iso en_US en_US
dc.relation.ispartof J Clin Invest
dc.relation.isversionof 10.1172/JCI40076
dc.subject Aminopeptidases
dc.subject Animals
dc.subject Centrosome
dc.subject Chromosome Mapping
dc.subject Cilia
dc.subject Family
dc.subject Female
dc.subject Genetic Diseases, Inborn
dc.subject Genome-Wide Association Study
dc.subject Humans
dc.subject Kidney
dc.subject Male
dc.subject Mitochondria
dc.subject Mitochondrial Proteins
dc.subject Rats
dc.subject Rats, Sprague-Dawley
dc.subject Renal Insufficiency
dc.subject Zebrafish
dc.title Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-3-0 en_US
duke.description.endpage 802 en_US
duke.description.issue 3 en_US
duke.description.startpage 791 en_US
duke.description.volume 120 en_US
dc.relation.journal Journal of Clinical Investigation en_US
pubs.issue 3
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Cell Biology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pediatrics
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pediatrics/Pediatrics, Neonatology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published
pubs.volume 120
dc.identifier.eissn 1558-8238

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