Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.
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.
O'Toole
John F
JF
Department of Pediatrics, University of Michigan, Ann Arbor, 48109-5646, USA.
Liu
Yangjian
Y
Davis
Erica E
EE
Westlake
Christopher J
CJ
Attanasio
Massimo
M
Otto
Edgar A
EA
Seelow
Dominik
D
Nurnberg
Gudrun
G
Becker
Christian
C
Nuutinen
Matti
M
Kärppä
Mikko
M
Ignatius
Jaakko
J
Uusimaa
Johanna
J
Pakanen
Salla
S
Jaakkola
Elisa
E
van den Heuvel
Lambertus P
LP
Fehrenbach
Henry
H
Wiggins
Roger
R
Goyal
Meera
M
Zhou
Weibin
W
Wolf
Matthias T F
MT
Wise
Eric
E
Helou
Juliana
J
Allen
Susan J
SJ
Murga-Zamalloa
Carlos A
CA
Ashraf
Shazia
S
Chaki
Moumita
M
Heeringa
Saskia
S
Chernin
Gil
G
Hoskins
Bethan E
BE
Chaib
Hassan
H
Gleeson
Joseph
J
Kusakabe
Takehiro
T
Suzuki
Takako
T
Isaac
R Elwyn
RE
Quarmby
Lynne M
LM
Tennant
Bryan
B
Fujioka
Hisashi
H
Tuominen
Hannu
H
Hassinen
Ilmo
I
Lohi
Hellevi
H
van Houten
Judith L
JL
Rotig
Agnes
A
Sayer
John A
JA
Rolinski
Boris
B
Freisinger
Peter
P
Madhavan
Sethu M
SM
Herzer
Martina
M
Madignier
Florence
F
Prokisch
Holger
H
Nurnberg
Peter
P
Jackson
Peter K
PK
Jackson
Peter
P
Khanna
Hemant
H
Katsanis
Nicholas
N
Hildebrandt
Friedhelm
F
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
D024101:Mitochondrial Proteins; D000626:Aminopeptidases; C000606138:XPNPEP3 protein, human; C022750:X-Pro aminopeptidase