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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2020

Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

Résumé

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.

Dates et versions

hal-03932210 , version 1 (10-01-2023)

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Simon Ramsbottom, Peter Thelwall, Katrina Wood, Gavin Clowry, Laura Devlin, et al.. Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome. Proceedings of the National Academy of Sciences of the United States of America, 2020, 117 (2), pp.1113-1118. ⟨10.1073/pnas.1912602117⟩. ⟨hal-03932210⟩
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