title: 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.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, 48109-5646, USA.
authors.forename: John F
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authors.lastname: O'Toole
authors.forename: Yangjian
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authors.lastname: Liu
authors.forename: Erica E
authors.initials: EE
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authors.forename: R Elwyn
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authors.forename: Lynne M
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authors.lastname: Quarmby
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authors.lastname: Tennant
authors.forename: Hisashi
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authors.lastname: Fujioka
authors.forename: Hannu
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authors.lastname: Tuominen
authors.forename: Ilmo
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authors.lastname: Hassinen
authors.forename: Hellevi
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authors.lastname: Lohi
authors.forename: Judith L
authors.initials: JL
authors.lastname: van Houten
authors.forename: Agnes
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authors.lastname: Rotig
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authors.lastname: Sayer
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authors.lastname: Rolinski
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authors.lastname: Freisinger
authors.forename: Sethu M
authors.initials: SM
authors.lastname: Madhavan
authors.forename: Martina
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authors.lastname: Herzer
authors.forename: Florence
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authors.lastname: Madignier
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Peter
authors.initials: P
authors.lastname: Nurnberg
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
authors.forename: Peter
authors.initials: P
authors.lastname: Jackson
authors.forename: Hemant
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authors.forename: Nicholas
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authors.lastname: Katsanis
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authors.lastname: Hildebrandt
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018385:Centrosome / Q000201:enzymology / Q000473:pathology; D002874:Chromosome Mapping / Q000379:methods; D002923:Cilia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005190:Family; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D000626:Aminopeptidases; C000606138:XPNPEP3 protein, human; C022750:X-Pro aminopeptidase