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

John F. O'Toole, Yangjian Liu, Erica E. Davis, Christopher J. Westlake, Massimo Attanasio, Edgar A. Otto, Dominik Seelow, Gudrun Nurnberg, Christian Becker, Matti Nuutinen, Mikko Kärppä, Jaakko Ignatius, Johanna Uusimaa, Salla Pakanen, Elisa Jaakkola, Lambertus P. Van Den Heuvel, Henry Fehrenbach, Roger Wiggins, Meera Goyal, Weibin ZhouMatthias T F Wolf, Eric Wise, Juliana Helou, Susan J. Allen, Carlos A. Murga-Zamalloa, Shazia Ashraf, Moumita Chaki, Saskia Heeringa, Gil Chernin, Bethan E. Hoskins, Hassan Chaib, Joseph Gleeson, Takehiro Kusakabe, Takako Suzuki, R. Elwyn Isaac, Lynne M. Quarmby, Bryan Tennant, Hisashi Fujioka, Hannu Tuominen, Ilmo Hassinen, Hellevi Lohi, Judith L. Van Houten, Agnes Rotig, John A. Sayer, Boris Rolinski, Peter Freisinger, Sethu M. Madhavan, Martina Herzer, Florence Madignier, Holger Prokisch, Peter Nurnberg, Peter Jackson, Hemant Khanna, Nicholas Katsanis, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)791-802
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number3
DOIs
StatePublished - Mar 1 2010

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Mitochondrial Proteins
Mutation
Cilia
Zebrafish
Mitochondria
Cystic Kidney Diseases
Phenotype
Centrosome
Proteins
Kidney Diseases
Proline
Genes
Renal Insufficiency
X-Pro aminopeptidase
Genome
Kidney
Ciliopathies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. / O'Toole, John F.; Liu, Yangjian; Davis, Erica E.; Westlake, Christopher J.; Attanasio, Massimo; Otto, Edgar A.; Seelow, Dominik; Nurnberg, Gudrun; Becker, Christian; Nuutinen, Matti; Kärppä, Mikko; Ignatius, Jaakko; Uusimaa, Johanna; Pakanen, Salla; Jaakkola, Elisa; Van Den Heuvel, Lambertus P.; Fehrenbach, Henry; Wiggins, Roger; Goyal, Meera; Zhou, Weibin; Wolf, Matthias T F; Wise, Eric; Helou, Juliana; Allen, Susan J.; Murga-Zamalloa, Carlos A.; Ashraf, Shazia; Chaki, Moumita; Heeringa, Saskia; Chernin, Gil; Hoskins, Bethan E.; Chaib, Hassan; Gleeson, Joseph; Kusakabe, Takehiro; Suzuki, Takako; Isaac, R. Elwyn; Quarmby, Lynne M.; Tennant, Bryan; Fujioka, Hisashi; Tuominen, Hannu; Hassinen, Ilmo; Lohi, Hellevi; Van Houten, Judith L.; Rotig, Agnes; Sayer, John A.; Rolinski, Boris; Freisinger, Peter; Madhavan, Sethu M.; Herzer, Martina; Madignier, Florence; Prokisch, Holger; Nurnberg, Peter; Jackson, Peter; Khanna, Hemant; Katsanis, Nicholas; Hildebrandt, Friedhelm.

In: Journal of Clinical Investigation, Vol. 120, No. 3, 01.03.2010, p. 791-802.

Research output: Contribution to journalArticle

O'Toole, JF, Liu, Y, Davis, EE, Westlake, CJ, Attanasio, M, Otto, EA, Seelow, D, Nurnberg, G, Becker, C, Nuutinen, M, Kärppä, M, Ignatius, J, Uusimaa, J, Pakanen, S, Jaakkola, E, Van Den Heuvel, LP, Fehrenbach, H, Wiggins, R, Goyal, M, Zhou, W, Wolf, MTF, Wise, E, Helou, J, Allen, SJ, Murga-Zamalloa, CA, Ashraf, S, Chaki, M, Heeringa, S, Chernin, G, Hoskins, BE, Chaib, H, Gleeson, J, Kusakabe, T, Suzuki, T, Isaac, RE, Quarmby, LM, Tennant, B, Fujioka, H, Tuominen, H, Hassinen, I, Lohi, H, Van Houten, JL, Rotig, A, Sayer, JA, Rolinski, B, Freisinger, P, Madhavan, SM, Herzer, M, Madignier, F, Prokisch, H, Nurnberg, P, Jackson, P, Khanna, H, Katsanis, N & Hildebrandt, F 2010, 'Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy', Journal of Clinical Investigation, vol. 120, no. 3, pp. 791-802. https://doi.org/10.1172/JCI40076
O'Toole, John F. ; Liu, Yangjian ; Davis, Erica E. ; Westlake, Christopher J. ; Attanasio, Massimo ; Otto, Edgar A. ; Seelow, Dominik ; Nurnberg, Gudrun ; Becker, Christian ; Nuutinen, Matti ; Kärppä, Mikko ; Ignatius, Jaakko ; Uusimaa, Johanna ; Pakanen, Salla ; Jaakkola, Elisa ; Van Den Heuvel, Lambertus P. ; Fehrenbach, Henry ; Wiggins, Roger ; Goyal, Meera ; Zhou, Weibin ; Wolf, Matthias T F ; Wise, Eric ; Helou, Juliana ; Allen, Susan J. ; Murga-Zamalloa, Carlos A. ; Ashraf, Shazia ; Chaki, Moumita ; Heeringa, Saskia ; Chernin, Gil ; Hoskins, Bethan E. ; Chaib, Hassan ; Gleeson, Joseph ; Kusakabe, Takehiro ; Suzuki, Takako ; Isaac, R. Elwyn ; Quarmby, Lynne M. ; Tennant, Bryan ; Fujioka, Hisashi ; Tuominen, Hannu ; Hassinen, Ilmo ; Lohi, Hellevi ; Van Houten, Judith L. ; Rotig, Agnes ; Sayer, John A. ; Rolinski, Boris ; Freisinger, Peter ; Madhavan, Sethu M. ; Herzer, Martina ; Madignier, Florence ; Prokisch, Holger ; Nurnberg, Peter ; Jackson, Peter ; Khanna, Hemant ; Katsanis, Nicholas ; Hildebrandt, Friedhelm. / Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 3. pp. 791-802.
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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.",
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T1 - Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

AU - O'Toole, John F.

AU - Liu, Yangjian

AU - Davis, Erica E.

AU - Westlake, Christopher J.

AU - Attanasio, Massimo

AU - Otto, Edgar A.

AU - Seelow, Dominik

AU - Nurnberg, Gudrun

AU - Becker, Christian

AU - Nuutinen, Matti

AU - Kärppä, Mikko

AU - Ignatius, Jaakko

AU - Uusimaa, Johanna

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AU - Jaakkola, Elisa

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AU - Goyal, Meera

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AU - Wolf, Matthias T F

AU - Wise, Eric

AU - Helou, Juliana

AU - Allen, Susan J.

AU - Murga-Zamalloa, Carlos A.

AU - Ashraf, Shazia

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AU - Heeringa, Saskia

AU - Chernin, Gil

AU - Hoskins, Bethan E.

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AU - Gleeson, Joseph

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AU - Suzuki, Takako

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AU - Quarmby, Lynne M.

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AU - Sayer, John A.

AU - Rolinski, Boris

AU - Freisinger, Peter

AU - Madhavan, Sethu M.

AU - Herzer, Martina

AU - Madignier, Florence

AU - Prokisch, Holger

AU - Nurnberg, Peter

AU - Jackson, Peter

AU - Khanna, Hemant

AU - Katsanis, Nicholas

AU - Hildebrandt, Friedhelm

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N2 - 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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