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NEK8 Mutations Affect Ciliary and Centrosomal Localization and May Cause Nephronophthisis

Edgar A. Otto^*, Melissa L. Trapp, Ulla T. Schultheiss^*, Juliana Helou^*, Lynne M. Quarmby and Friedhelm Hildebrandt^*,

Departments of ^* Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, Michigan; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada

Correspondence: Dr. Friedhelm Hildebrandt, University of Michigan Health System, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5646. Phone: 734-615-7285 (office), 734-615-7895, 734-615-7896 (laboratories); Fax: 734-615-1386, 734-615-7770; E-mail: fhilde{at}umich.edu

Received for publication April 20, 2007. Accepted for publication August 15, 2007.

Nephronophthisis, an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first 3 decades of life. Causative mutations in 8 genes (NPHP1–8) have been identified, and homologous mouse models for NPHP2/INVS and NPHP3 have been described. The jck mouse is another model of recessive cystic kidney disease, and this mouse harbors a missense mutation, G448V, in the highly conserved RCC1 domain of Nek8. We hypothesized that mutations in NEK8 might cause nephronophthisis in humans, so we performed mutational analysis in a worldwide cohort of 588 patients. We identified 3 different amino acid changes that were conserved through evolution (L330F, H425Y, and A497P) and that were absent from at least 80 ethnically matched controls. All 3 mutations were within RCC1 domains, and the mutation H425Y was positioned within the same RCC1 repeat as the mouse jck mutation. To test the functional significance of these mutations, we introduced them into full-length mouse Nek8 GFP-tagged cDNA constructs. We transiently overexpressed the constructs in inner medullary collecting duct cells (IMCD-3 cell line) and compared the subcellular localization of mutant Nek8 to wild-type Nek8. All mutant forms of Nek8 showed defects in ciliary localization to varying degrees; the H431Y mutant (human H425Y) was completely absent from cilia and the amount localized to centrosomes was decreased. Overexpression of these mutants did not affect overall ciliogenesis, mitosis, or centriole number. Our genetic and functional data support the assumption that mutations in NEK8 cause nephronophthisis (NPHP9), adding another link between proteins mutated in cystic kidney disease and their localization to cilia and centrosomes.

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Too Much of a Good Thing: Does Nek8 Link Polycystic Kidney Disease and Nephronophthisis?

Yiqiang Cai and Stefan Somlo
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This article has been cited by other articles:

				F. Hildebrandt, M. Attanasio, and E. Otto Nephronophthisis: Disease Mechanisms of a Ciliopathy J. Am. Soc. Nephrol., January 1, 2009; 20(1): 23 - 35. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673