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Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

Lookup NU author(s): Dr Simon Ramsbottom, Professor Peter Thelwall, Dr Gavin Clowry, Laura Devlin, Dr Helena Spiewak, Professor Heather Cordell, Professor John Sayer, 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.

Publication metadata

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


DOI: 10.1073/pnas.1912602117

PubMed id: 31879347


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