Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

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-deficie...

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Autores principales: Ramsbottom, Simon A., Thelwall, Peter E., Wood, Katrina M., Clowry, Gavin J., Devlin, Laura A., Silbermann, Flora, Spiewak, Helena L., Shril, Shirlee, Molinari, Elisa, Hildebrandt, Friedhelm, Gunay-Aygun, Meral, Saunier, Sophie, Cordell, Heather J., Sayer, John A., Miles, Colin G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969532/
https://www.ncbi.nlm.nih.gov/pubmed/31879347
http://dx.doi.org/10.1073/pnas.1912602117
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author Ramsbottom, Simon A.
Thelwall, Peter E.
Wood, Katrina M.
Clowry, Gavin J.
Devlin, Laura A.
Silbermann, Flora
Spiewak, Helena L.
Shril, Shirlee
Molinari, Elisa
Hildebrandt, Friedhelm
Gunay-Aygun, Meral
Saunier, Sophie
Cordell, Heather J.
Sayer, John A.
Miles, Colin G.
author_facet Ramsbottom, Simon A.
Thelwall, Peter E.
Wood, Katrina M.
Clowry, Gavin J.
Devlin, Laura A.
Silbermann, Flora
Spiewak, Helena L.
Shril, Shirlee
Molinari, Elisa
Hildebrandt, Friedhelm
Gunay-Aygun, Meral
Saunier, Sophie
Cordell, Heather J.
Sayer, John A.
Miles, Colin G.
author_sort Ramsbottom, Simon A.
collection PubMed
description 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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spelling pubmed-69695322020-01-27 Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome Ramsbottom, Simon A. Thelwall, Peter E. Wood, Katrina M. Clowry, Gavin J. Devlin, Laura A. Silbermann, Flora Spiewak, Helena L. Shril, Shirlee Molinari, Elisa Hildebrandt, Friedhelm Gunay-Aygun, Meral Saunier, Sophie Cordell, Heather J. Sayer, John A. Miles, Colin G. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2020-01-14 2019-12-26 /pmc/articles/PMC6969532/ /pubmed/31879347 http://dx.doi.org/10.1073/pnas.1912602117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Ramsbottom, Simon A.
Thelwall, Peter E.
Wood, Katrina M.
Clowry, Gavin J.
Devlin, Laura A.
Silbermann, Flora
Spiewak, Helena L.
Shril, Shirlee
Molinari, Elisa
Hildebrandt, Friedhelm
Gunay-Aygun, Meral
Saunier, Sophie
Cordell, Heather J.
Sayer, John A.
Miles, Colin G.
Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome
title Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome
title_full Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome
title_fullStr Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome
title_full_unstemmed Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome
title_short Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome
title_sort mouse genetics reveals barttin as a genetic modifier of joubert syndrome
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969532/
https://www.ncbi.nlm.nih.gov/pubmed/31879347
http://dx.doi.org/10.1073/pnas.1912602117
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