Browse by author
Lookup NU author(s): Dr Simon RamsbottomORCiD, Professor Peter Thelwall, Dr Katrina Wood, Dr Gavin ClowryORCiD, Laura Devlin, Dr Helena Spiewak, Dr Elisa MolinariORCiD, Professor Heather Cordell, Professor John SayerORCiD, Dr Colin Miles
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Copyright © 2020 the Author(s). Published by PNAS.Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.
Author(s): Ramsbottom SA, Thelwall PE, Wood KM, Clowry GJ, Devlin LA, Silbermann F, Spiewak HL, Shril S, Molinari E, Hildebrandt F, Gunay-Aygun M, Saunier S, Cordell HJ, Sayer JA, Miles CG
Publication type: Article
Publication status: Published
Journal: Proceedings of the National Academy of Sciences of the United States of America
Year: 2020
Volume: 117
Issue: 2
Pages: 1113-1118
Print publication date: 14/01/2020
Online publication date: 26/12/2019
Acceptance date: 02/04/2019
Date deposited: 07/02/2020
ISSN (print): 0027-8424
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: https://doi.org/10.1073/pnas.1912602117
DOI: 10.1073/pnas.1912602117
PubMed id: 31879347
Altmetrics provided by Altmetric
