A novel mutation causing nephronophthisis in the Lewis polycystic kidney rat localises to a conserved RCC1 domain in Nek8Reportar como inadecuado

A novel mutation causing nephronophthisis in the Lewis polycystic kidney rat localises to a conserved RCC1 domain in Nek8 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Genomics

, 13:393

Human and rodent genomic


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 GQRCLG 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.

KeywordsCilia Directed next generation sequencing Electron microscopy Genome capture Immunohistochemistry Nek8 NPHP Polycystic kidney disease AbbreviationsBC1Backcross

BNBrown Norway


HandEHaematoxylin and eosin

LPKLewis Polycystic Kidney

LODLogarithm of odds


NIMANever in mitosis gene a- related kinase 8 Nek8

PBPhosphate buffer

PKDPolycystic kidney disease

PCRPolymerase chain reaction

QTLQuantitative trait locus

RanRas-related nuclear protein

RCC1Regulator of chromosome condensation 1

F2Second filial

SNPSingle nucleotide polymorphisms

WKYWistar Kyoto.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-13-393 contains supplementary material, which is available to authorized users.

John K McCooke, Rudi Appels and Jacqueline K Phillips contributed equally to this work.

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Autor: John K McCooke - Rudi Appels - Roberto A Barrero - Alice Ding - Justyna E Ozimek-Kulik - Mathew I Bellgard - Grant Mora

Fuente: https://link.springer.com/

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