Clowry GJ

Cordell HJ

Devlin LA

Gunay-Aygun M

Hildebrandt F

Miles CG

Molinari E

Ramsbottom SA

Saunier S

Sayer JA

Shril S

Silbermann F

Spiewak HL

Thelwall PE

Wood KM

Copyright \ua9 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

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Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

https://eprint.ncl.ac.uk/file_store/production/263167/D220B239-CF07-40C4-B340-DFD78721D588.pdf

Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

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