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O'Toole, J.F.* ; Liu, Y.J.* ; Davis, E.E.* ; Westlake, C.J.* ; Attanasio, M.* ; Otto, E.A.* ; Seelow, D.* ; Nurnberg, G.* ; Becker, C.* ; Nuutinen, M.* ; Kärppa, M.* ; Ignatius, J.* ; Uusimaa, J.* ; Pakanen, S.* ; Jaakkola, E.* ; van den Heuvel, L.P.* ; Fehrenbach, H.* ; Wiggins, R.* ; Goyal, M.B.* ; Zhou, W.* ; Wolf, M.T.F.* ; Wise, E.* ; Helou, J.* ; Allen, S.J.* ; Murga-Zamalloa, C.A.* ; Ashraf, S.* ; Chaki, M.* ; Heeringa, S.* ; Chernin, G.* ; Hoskins, B.E.* ; Chaib, H.* ; Gleeson, J.* ; Kusakabe, T.* ; Suzuki, T.* ; Isaac, R.E.* ; Quarmby, L.M.* ; Tennant, B.* ; Fujioka, H.* ; Tuominen, H.* ; Hassinen, I.* ; Lohi, H.* ; van Houten, J.L.* ; Rotig, A.* ; Sayer, J.A.* ; Rolinski, B.* ; Freisinger, P.* ; Madhavan, S.M.* ; Herzer, M. ; Madignier, F. ; Prokisch, H. ; Nürnberg, P.* ; Jackson, P.K.* ; Khanna, H.* ; Katsanis, N.* ; Hildebrandt, F.*

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

J. Clin. Invest. 120, 791-802 (2010)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Aminopeptidases/genetics; Aminopeptidases/metabolism*; Animals; Centrosome/enzymology; Centrosome/pathology; Chromosome Mapping/methods; Cilia/enzymology; Cilia/genetics; Cilia/pathology; Family; Female; Genetic Diseases, Inborn/enzymology*; Genetic Diseases, Inborn/genetics; Genetic Diseases, Inborn/pathology; Genome-Wide Association Study/methods; Humans; Kidney/enzymology*; Kidney/pathology; Kidney Failure/enzymology*; Kidney Failure/genetics; Kidney Failure/pathology; Male; Mitochondria/enzymology*; Mit; BARDET-BIEDL-SYNDROME; PLANAR CELL POLARITY; AMINOPEPTIDASE-P; JOUBERT-SYNDROME; RETINAL DEGENERATION; CENTROSOMAL PROTEIN; RESPIRATORY-CHAIN; MECKEL-SYNDROME; DOMAIN PROTEIN; KIDNEY-DISEASE
Language
Publication Year 2010
HGF-reported in Year 2010
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 120, Issue: 3, Pages: 791-802 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
PubMed ID 20179356
DOI 10.1172/JCI40076
WOS ID WOS:000275272700017
Scopus ID 77949865316
Erfassungsdatum 2010-10-15
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