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.
Type
Journal articleSubject
AminopeptidasesAnimals
Centrosome
Chromosome Mapping
Cilia
Family
Female
Genetic Diseases, Inborn
Genome-Wide Association Study
Humans
Kidney
Male
Mitochondria
Mitochondrial Proteins
Rats
Rats, Sprague-Dawley
Renal Insufficiency
Zebrafish
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https://hdl.handle.net/10161/4325Published Version (Please cite this version)
10.1172/JCI40076Publication Info
O'Toole, JF; Liu, Y; Davis, EE; Westlake, CJ; Attanasio, M; Otto, EA; ... Hildebrandt,
F (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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
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 addr
Nicholas Katsanis
Jean and George W. Brumley, Jr., M.D. Professor of Developmental Biology
Weibin Zhou
Assistant Professor in Medicine
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