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Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

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.

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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