PUBLICATION
Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy
- Authors
- O'Toole, J.F., Liu, Y., Davis, E.E., Westlake, C.J., Attanasio, M., Otto, E.A., Seelow, D., Nurnberg, G., Becker, C., Nuutinen, M., Kärppä, M., Ignatius, J., Uusimaa, J., Pakanen, S., Jaakkola, E., van den Heuvel, L.P., Fehrenbach, H., Wiggins, R., Goyal, M., Zhou, W., Wolf, M.T., 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., Nurnberg, P., Jackson, P., Khanna, H., Katsanis, N., and Hildebrandt, F.
- ID
- ZDB-PUB-100302-5
- Date
- 2010
- Source
- J. Clin. Invest. 120(3): 791-802 (Journal)
- Registered Authors
- Davis, Erica, Katsanis, Nicholas, Khanna, Hemant, Zhou, Weibin
- Keywords
- none
- MeSH Terms
-
- 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
- Male
- Mitochondria/enzymology*
- Mitochondria/pathology
- Mitochondrial Proteins/genetics
- Mitochondrial Proteins/metabolism*
- Rats
- Rats, Sprague-Dawley
- Renal Insufficiency/enzymology*
- Renal Insufficiency/genetics
- Renal Insufficiency/pathology
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 20179356 Full text @ J. Clin. Invest.
Citation
O'Toole, J.F., Liu, Y., Davis, E.E., Westlake, C.J., Attanasio, M., Otto, E.A., Seelow, D., Nurnberg, G., Becker, C., Nuutinen, M., Kärppä, M., Ignatius, J., Uusimaa, J., Pakanen, S., Jaakkola, E., van den Heuvel, L.P., Fehrenbach, H., Wiggins, R., Goyal, M., Zhou, W., Wolf, M.T., 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., Nurnberg, P., Jackson, P., Khanna, H., Katsanis, N., and Hildebrandt, F. (2010) Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J. Clin. Invest.. 120(3):791-802.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping