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.
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Review Series

Genetic disorders of nuclear receptors

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

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Figure 2

Molecular mechanisms of disrupted NR action.

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Molecular mechanisms of disrupted NR action. (A) Mechanisms whereby NR g...
(A) Mechanisms whereby NR gene and protein changes can alter function. Gene deletion or mutations causing mRNA instability or impairing key cellular functions can cause loss of function (left). Gain of receptor function may occur due to duplication of an NR genomic locus (e.g., NR0B1) or LBD mutation (right). (B) In several disorders heterozygous receptor mutants (e.g., TRβ, TRα, PPARγ, VDR) inhibit the action of their wild-type counterparts in a dominant-negative manner. In contrast to the wild-type receptor, either defective binding of ligand (L) or recruitment of coactivator (CoA) by a mutant (MUT) receptor impairs its dissociation of corepressor (CoR), mediating constitutive repression of target gene expression. HRE, hormone response element. (C) Alopecia is not a universal feature of hereditary vitamin D resistance. It is associated with VDR mutations that disrupt DNA binding, that cause loss of heterodimerization with RXR, or that cause loss of receptor expression, but not with variants exhibiting impaired ligand binding affinity or coactivator recruitment. Repression of target genes by unliganded wild-type receptor maintains a normal hair growth cycle, and the loss of such inhibition that accompanies a subset of VDR mutants (right) is thought to mediate this variable phenotype.