Genetic disorders of nuclear receptors.

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

Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α

Mutations in thyroid hormone receptor a (TRα), a ligand-inducible transcription factor, cause resistance to thyroid hormone a (RTHα). This disorder is characterized by tissue-specific hormone refractoriness and hypothyroidism due to the inhibition of target gene expression by mutant TRa-corepressor complexes. Using biophysical approaches, we show that RTHa-associated TRa mutants devoid of ligand-dependent transcription activation function unexpectedly retain the ability to bind thyroid hormone. Visualization of the ligand T3 within the crystal structure of a prototypic TRa mutant validates this notion. This finding prompted the synthesis of different thyroid hormone analogues, identifying a lead compound, ES08, which dissociates corepressor from mutant human TRa more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHa and induces target gene expression in TRa mutation-containing cells from an RTHa patient more effectively than T3. Our observations provide proof of principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRa-corepressor complex for treatment of RTHa.</p