Journal article
A novel mutation causing nephronophthisis in the Lewis polycystic kidney rat localises to a conserved RCC1 domain in Nek8
BMC Genomics, Vol.13(1)
2012
Abstract
Background
Nephronophthisis (NPHP) as a cause of cystic kidney disease is the most common genetic cause of progressive renal failure in children and young adults. NPHP is characterized by abnormal and/or loss of function of proteins associated with primary cilia. Previously, we characterized an autosomal recessive phenotype of cystic kidney disease in the Lewis Polycystic Kidney (LPK) rat.
Results
In this study, quantitative trait locus analysis was used to define a ~1.6Mbp region on rat chromosome 10q25 harbouring the lpk mutation. Targeted genome capture and next-generation sequencing of this region identified a non-synonymous mutation R650C in the NIMA (never in mitosis gene a)- related kinase 8 ( Nek8) gene. This is a novel Nek8 mutation that occurs within the regulator of chromosome condensation 1 (RCC1)-like region of the protein. Specifically, the R650C substitution is located within a G[QRC]LG repeat motif of the predicted seven bladed beta-propeller structure of the RCC1 domain. The rat Nek8 gene is located in a region syntenic to portions of human chromosome 17 and mouse 11. Scanning electron microscopy confirmed abnormally long cilia on LPK kidney epithelial cells, and fluorescence immunohistochemistry for Nek8 protein revealed altered cilia localisation.
Conclusions
When assessed relative to other Nek8 NPHP mutations, our results indicate the whole propeller structure of the RCC1 domain is important, as the different mutations cause comparable phenotypes. This study establishes the LPK rat as a novel model system for NPHP and further consolidates the link between cystic kidney disease and cilia proteins.
Details
- Title
- A novel mutation causing nephronophthisis in the Lewis polycystic kidney rat localises to a conserved RCC1 domain in Nek8
- Authors/Creators
- J.K. McCooke (Author/Creator)R. Appels (Author/Creator)R.A. Barrero (Author/Creator)A. Ding (Author/Creator)J.E. Ozimek-Kulik (Author/Creator)M.I. Bellgard (Author/Creator)G. Morahan (Author/Creator)J.K. Phillips (Author/Creator)
- Publication Details
- BMC Genomics, Vol.13(1)
- Publisher
- BioMed Central
- Identifiers
- 991005544601907891
- Copyright
- © 2012 McCooke et al
- Murdoch Affiliation
- Centre for Comparative Genomics
- Language
- English
- Resource Type
- Journal article
- Note
- This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.108 Molecular & Cell Biology - Cancer & Development
- 1.108.1327 Ciliopathies
- Web Of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics