Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

Simon A. Ramsbottom, Peter E. Thelwall, Katrina M. Wood, Gavin J. Clowry, Laura A. Devlin, Flora Silbermann, Helena L. Spiewak, Shirlee Shril, Elisa Molinari, Friedhelm Hildebrandt, Meral Gunay-Aygun, Sophie Saunier, Heather J. Cordell, John A. Sayer, Colin G. Miles

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1113-1118
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
StatePublished - Jan 14 2020


  • Barttin
  • Ciliopathy
  • Genetics
  • Joubert syndrome
  • Modifier

ASJC Scopus subject areas

  • General


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