A novel mutation causing nephronophthisis in the Lewis polycystic kidney rat localises to a conserved RCC1 domain in Nek8 View Full Text


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Article Info

DATE

2012-08-16

AUTHORS

John K McCooke, Rudi Appels, Roberto A Barrero, Alice Ding, Justyna E Ozimek-Kulik, Mathew I Bellgard, Grant Morahan, Jacqueline K Phillips

ABSTRACT

BackgroundNephronophthisis (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.ResultsIn 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.ConclusionsWhen 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. More... »

PAGES

393

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/1471-2164-13-393

    DOI

    http://dx.doi.org/10.1186/1471-2164-13-393

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/22899815


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    39 schema:description BackgroundNephronophthisis (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.ResultsIn 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.ConclusionsWhen 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.
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    46 LPK rats
    47 Lewis polycystic kidney rats
    48 NEK8
    49 NIMA
    50 NPHP
    51 Nek8 gene
    52 RCC1 domain
    53 ResultsIn
    54 adults
    55 analysis
    56 autosomal recessive phenotype
    57 beta-propeller structure
    58 capture
    59 cause
    60 cells
    61 children
    62 chromosome 10q25
    63 chromosome 17
    64 chromosome condensation 1
    65 cilia
    66 cilia proteins
    67 common genetic cause
    68 comparable phenotypes
    69 condensation 1
    70 cystic kidney disease
    71 different mutations
    72 disease
    73 domain
    74 electron microscopy
    75 epithelial cells
    76 failure
    77 fluorescence immunohistochemistry
    78 function
    79 genes
    80 genetic cause
    81 genome capture
    82 human chromosome 17
    83 immunohistochemistry
    84 kidney disease
    85 kidney epithelial cells
    86 kidney rats
    87 like region
    88 link
    89 localisation
    90 localises
    91 locus analysis
    92 long cilia
    93 loss
    94 loss of function
    95 microscopy
    96 mitosis gene
    97 model system
    98 motif
    99 mouse 11
    100 mutations
    101 nephronophthisis
    102 next-generation sequencing
    103 novel model system
    104 novel mutations
    105 phenotype
    106 polycystic kidney (PCK) rat
    107 portion
    108 primary cilia
    109 progressive renal failure
    110 propeller structure
    111 protein
    112 quantitative trait locus (QTL) analysis
    113 rats
    114 recessive phenotype
    115 region
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    117 regulator
    118 renal failure
    119 repeat motifs
    120 results
    121 sequencing
    122 structure
    123 study
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    125 syntenic
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