Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome.

Autor:	Ramsbottom SA; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne NE1 3BZ, United Kingdom., Thelwall PE; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne NE1 3BZ, United Kingdom.; Newcastle Magnetic Resonance Centre, Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom., Wood KM; The Histopathology Department, The Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne NE7 7DN, United Kingdom., Clowry GJ; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom., Devlin LA; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne NE1 3BZ, United Kingdom., Silbermann F; Laboratory of Hereditary Kidney Disease, Imagine Institute, INSERM U1163, Université de Paris, 75015 Paris, France., Spiewak HL; Northern Genetics Service, International Centre for Life, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, United Kingdom., Shril S; Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115., Molinari E; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne NE1 3BZ, United Kingdom., Hildebrandt F; Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115., Gunay-Aygun M; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Saunier S; Laboratory of Hereditary Kidney Disease, Imagine Institute, INSERM U1163, Université de Paris, 75015 Paris, France., Cordell HJ; Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom., Sayer JA; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne NE1 3BZ, United Kingdom; john.sayer@ncl.ac.uk colin.miles@ncl.ac.uk.; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.; National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne NE4 5PL, United Kingdom., Miles CG; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne NE1 3BZ, United Kingdom; john.sayer@ncl.ac.uk colin.miles@ncl.ac.uk.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jan 14; Vol. 117 (2), pp. 1113-1118. Date of Electronic Publication: 2019 Dec 26.
DOI:	10.1073/pnas.1912602117
Abstrakt:	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. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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