Show simple item record

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

dc.contributor.author O'Toole, JF
dc.contributor.author Liu, Y
dc.contributor.author Davis, EE
dc.contributor.author Westlake, CJ
dc.contributor.author Attanasio, M
dc.contributor.author Otto, EA
dc.contributor.author Seelow, D
dc.contributor.author Nurnberg, G
dc.contributor.author Becker, C
dc.contributor.author Nuutinen, M
dc.contributor.author Kärppä, M
dc.contributor.author Ignatius, J
dc.contributor.author Uusimaa, J
dc.contributor.author Pakanen, S
dc.contributor.author Jaakkola, E
dc.contributor.author van den Heuvel, LP
dc.contributor.author Fehrenbach, H
dc.contributor.author Wiggins, R
dc.contributor.author Goyal, M
dc.contributor.author Zhou, W
dc.contributor.author Wolf, MT
dc.contributor.author Wise, E
dc.contributor.author Helou, J
dc.contributor.author Allen, SJ
dc.contributor.author Murga Zamalloa, CA
dc.contributor.author Ashraf, S
dc.contributor.author Chaki, M
dc.contributor.author Heeringa, S
dc.contributor.author Chernin, G
dc.contributor.author Hoskins, BE
dc.contributor.author Chaib, H
dc.contributor.author Gleeson, J
dc.contributor.author Kusakabe, T
dc.contributor.author Suzuki, T
dc.contributor.author Isaac, RE
dc.contributor.author Quarmby, LM
dc.contributor.author Tennant, B
dc.contributor.author Fujioka, H
dc.contributor.author Tuominen, H
dc.contributor.author Hassinen, I
dc.contributor.author Lohi, H
dc.contributor.author van Houten, JL
dc.contributor.author Rotig, A
dc.contributor.author Sayer, JA
dc.contributor.author Rolinski, B
dc.contributor.author Freisinger, P
dc.contributor.author Madhavan, SM
dc.contributor.author Herzer, M
dc.contributor.author Madignier, F
dc.contributor.author Prokisch, H
dc.contributor.author Nurnberg, P
dc.contributor.author Jackson, PK
dc.contributor.author Jackson, P
dc.contributor.author Khanna, H
dc.contributor.author Katsanis, N
dc.contributor.author Hildebrandt, F
dc.coverage.spatial United States
dc.date.accessioned 2011-06-21T17:27:54Z
dc.date.issued 2010-03
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20179356
dc.identifier 40076
dc.identifier.uri https://hdl.handle.net/10161/4325
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.language eng
dc.language.iso en_US
dc.publisher American Society for Clinical Investigation
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
dc.type Journal article
duke.contributor.id Davis, EE|0520136
duke.contributor.id Zhou, W|0812546
duke.contributor.id Katsanis, N|0510002
dc.description.version Version of Record
duke.date.pubdate 2010-3-0
duke.description.issue 3
duke.description.volume 120
dc.relation.journal Journal of Clinical Investigation
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20179356
pubs.begin-page 791
pubs.end-page 802
pubs.issue 3
pubs.organisational-group Basic Science Departments
pubs.organisational-group Cell Biology
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Pediatrics
pubs.organisational-group Pediatrics, Neonatology
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 120
dc.identifier.eissn 1558-8238
duke.contributor.orcid Davis, EE|0000-0002-2412-8397


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record