Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
Genetic disorders of nuclear receptors
John C. Achermann, … , Louise Fairall, Krishna Chatterjee
John C. Achermann, … , Louise Fairall, Krishna Chatterjee
Published April 3, 2017
Citation Information: J Clin Invest. 2017;127(4):1181-1192. https://doi.org/10.1172/JCI88892.
View: Text | PDF
Category: Review Series

Genetic disorders of nuclear receptors

  • Text
  • PDF
Abstract

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.

Authors

John C. Achermann, John Schwabe, Louise Fairall, Krishna Chatterjee

×

Figure 3

Structural modeling of NR mutations.(A) Modeling (PDB 2H77 TRα, PDB 1KKQ SMRT) shows that mutation of residues (red spheres) in the carboxyterminal region of TRα, which prematurely truncate helix 11 or 12 (left), facilitate its ability to accommodate corepressor (SMRT, blue) within a groove at the receptor surface (right).

Options: View larger image (or click on image) Download as PowerPoint
Structural modeling of NR mutations.(A) Modeling (PDB 2H77 TRα, PDB 1KKQ...
(B) Modeling (PDB 1RK3, VDR bound to DRIP 205 coactivator) shows that a glutamic acid residue (left; red sphere) hydrogen bonds with the peptide backbone of coactivator (middle; green). Mutation to lysine abolishes this interaction (right).(C) Modeling (PDB 5HCV MR, PDB 5L7E S810L mutant MR) shows that wild-type receptor, with serine at position 810, accommodates aldosterone via hydrogen bonding with steroid (middle; red dotted line), whereas mutant MR with a leucine substitution accommodates progesterone via van der Waals interaction with steroid (right; blue dotted line). (D) Modeling (PDB 2FF0) shows SF-1/NR5A1 bound to DNA. R92 makes an extensive hydrogen bond network in the minor groove to support monomeric binding. This interaction is disrupted by the R92W mutation due to the presence of an indole side group.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts