Genetic disorders of nuclear receptors
John C. Achermann,1 John Schwabe,2 Louise Fairall,2 and Krishna Chatterjee3
1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
2Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.
3Wellcome Trust—MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Address correspondence to: V. Krishna K. Chatterjee, University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke’s Hospital, Cambridge, CB2 0QQ. Phone: 44.1223.336842; E-mail: kkc1@medschl.cam.ac.uk.
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1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
2Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.
3Wellcome Trust—MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Address correspondence to: V. Krishna K. Chatterjee, University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke’s Hospital, Cambridge, CB2 0QQ. Phone: 44.1223.336842; E-mail: kkc1@medschl.cam.ac.uk.
Find articles by Schwabe, J. in: JCI | PubMed | Google Scholar
1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
2Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.
3Wellcome Trust—MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Address correspondence to: V. Krishna K. Chatterjee, University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke’s Hospital, Cambridge, CB2 0QQ. Phone: 44.1223.336842; E-mail: kkc1@medschl.cam.ac.uk.
Find articles by Fairall, L. in: JCI | PubMed | Google Scholar
1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
2Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.
3Wellcome Trust—MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Address correspondence to: V. Krishna K. Chatterjee, University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke’s Hospital, Cambridge, CB2 0QQ. Phone: 44.1223.336842; E-mail: kkc1@medschl.cam.ac.uk.
Find articles by Chatterjee, K. in: JCI | PubMed | Google Scholar
First published April 3, 2017 - More info
J Clin Invest. 2017;127(4):1181–1192. doi:10.1172/JCI88892.
Copyright © 2017, American Society for Clinical Investigation
Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with “monogenic” conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.
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