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Molecular mechanisms of disrupted NR action. (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.
Source publication
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 i...
Contexts in source publication
Context 1
... with their location, most TRβ mutations impair hormone binding or (rarely) coactivator recruitment and inhib- it action of their wild-type counterparts in a dominant-negative manner ( Figure 2B). Receptor functional regions (such as DNA binding, dimerization, and corepressor binding) are devoid of naturally occurring TRβ mutations, with RTHβ variants clustering within hotspots within the LBD (1). Homozygous THRB deletion mediated RTHβ in the first two recorded siblings with this disor- der, who also had audiovisual abnormalities (2). Biallelic missense mutations were present in five other recessively inherited cases (3). In roughly 15% of people with biochemical features of RTHβ, no THRB defect can be identified; in such situations, alterations in co-regulators or other factors mediating TH action have been postulated (1). Triiodothyroacetic acid treatment, a centrally act- ing TH analogue that lowers TH levels, can control thyrotoxic fea- tures of the ...
Context 2
... THRA mutations disrupt TRα1 function either markedly or partially and inhibit wild-type receptor action in a dominant-negative manner via a mechanism involving enhanced corepressor recruitment and target gene repression ( Figure 2B, Fig- ure 3A, and ref. 5). Some THRA defects also involve the carboxy- terminally divergent, non-hormone-binding TRα2 isoform, with no discernible added clinical phenotype or gain or loss of function attributable to the TRα2 variant (6). Consonant with resemblance of the RTHα phenotype to some features seen in conventional hypothyroidism, T4 therapy reverses metabolic abnormalities and improves growth, constipation, dyspraxia, and ...
Context 3
... has been almost 30 years since the first human nuclear recep- tor (NR) disorders were characterized at the molecular level (Fig- ure 1). Since then, disorders associated with genetic defects in 20 of the 48 known human NRs have been identified (Figure 1 and Tables 1 and 2). In this Review we provide a brief overview of the range of human NR-associated diseases reported to date and highlight some of the key pathogenic mechanisms involved ( Figure 2A). Our focus is on well-established monogenic germline disorders. We will not cover the role of somatic NR variations or fusion genes in cancer, nor associations found in ...
Context 4
... then, disorders associated with genetic defects in 20 of the 48 known human NRs have been identified (Figure 1 and Tables 1 and 2). In this Review we provide a brief overview of the range of human NR-associated diseases reported to date and highlight some of the key pathogenic mechanisms involved ( Figure 2A). Our focus is on well-established monogenic germline disorders. ...
Context 5
... with their location, most TRβ mutations impair hormone binding or (rarely) coactivator recruitment and inhib- it action of their wild-type counterparts in a dominant-negative manner ( Figure 2B). Receptor functional regions (such as DNA binding, dimerization, and corepressor binding) are devoid of naturally occurring TRβ mutations, with RTHβ variants clustering within hotspots within the LBD (1). ...
Context 6
... THRA mutations disrupt TRα1 function either markedly or partially and inhibit wild-type receptor action in a dominant-negative manner via a mechanism involving enhanced corepressor recruitment and target gene repression ( Figure 2B, Fig- ure 3A, and ref. 5). Some THRA defects also involve the carboxy- terminally divergent, non-hormone-binding TRα2 isoform, with no discernible added clinical phenotype or gain or loss of function attributable to the TRα2 variant (6). ...
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Citations
... Thus, activated NRs have the capability to translate both environmental changes and intracellular metabolic alterations into distinct physiological responses by regulating gene expression. Malfunctioning NRs cause a wide array of diseases and inherited disorders [43,86]. Their ligand-responsive nature renders NRs susceptible to modulation by synthetic ligands, which currently make up nearly 16% of all FDA-approved drugs [87]. . ...
Disease-modifying strategies for Parkinson disease (PD), the most common synucleinopathy, represent a critical unmet medical need. Accumulation of the neuronal protein alpha-synuclein (αS) and abnormal lipid metabolism have each been implicated in PD pathogenesis. Here, we elucidate how retinoid-X-receptor (RXR) nuclear receptor signaling impacts these two aspects of PD pathogenesis. We find that activated RXR differentially regulates fatty acid desaturases, significantly reducing the transcript levels of the largely brain-specific desaturase SCD5 in human cultured neural cells and PD patient-derived neurons. This was associated with reduced perilipin-2 protein levels in patient neurons, reversal of αS-induced increases in lipid droplet (LD) size, and a reduction of triglyceride levels in human cultured cells. With regard to αS proteostasis, our study reveals that RXR agonism stimulates lysosomal clearance of αS. Our data support the involvement of Polo-like kinase 2 activity and αS S129 phosphorylation in mediating this benefit. The lowering of cellular αS levels was associated with reduced cytotoxicity. Compared to RXR activation, the RXR antagonist HX531 had the opposite effects on LD size, SCD, αS turnover, and cytotoxicity, all supporting pathway specificity. Together, our findings show that RXR-activating ligands can modulate fatty acid metabolism and αS turnover to confer benefit in cellular models of PD, including patient neurons. We offer a new paradigm to investigate nuclear receptor ligands as a promising strategy for PD and related synucleinopathies.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00018-024-05373-2.
... Functionally, NRs engage in critical physiological programs, including embryonic development, the maintenance of differentiated cellular phenotypes, metabolism, and cell death. Dysfunctions in NR signaling lead to proliferative, reproductive, and metabolic diseases such as cancer, infertility, obesity, and diabetes [63,64]. The druggable nature of NRs has made them attractive targets for various human diseases, resulting in the development of receptor-selective full, partial, and inverse agonists, as well as compounds that activate only a subset of functions induced by the cognate ligand, and molecules that act in a cell-type-selective manner [65,66]. ...
The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format. The top five NRs associated with the highest number of safety alerts from peer-reviewed journals, regulatory agency communications, congresses/conferences, clinical trial registries, and company communications were the Glucocorticoid Receptor (GR, 18,328), Androgen Receptor (AR, 18,219), Estrogen Receptor (ER, 12,028), Retinoic acid receptors (RAR, 10,450), and Pregnane X receptor (PXR, 8044). Toxicities associated with NR modulation include hepatotoxicity, cardiotoxicity, endocrine disruption, carcinogenicity, metabolic disorders, and neurotoxicity. These toxicities often arise from the dysregulation of receptors like Peroxisome proliferator-activated receptors (PPARα, PPARγ), the ER, PXR, AR, and GR. This dysregulation leads to various health issues, including liver enlargement, hepatocellular carcinoma, heart-related problems, hormonal imbalances, tumor growth, metabolic syndromes, and brain function impairment. Gene expression analysis using heatmaps for human and rat tissues complemented the functional modulation of NRs associated with the reported toxicities. Interestingly, certain NRs showed ubiquitous expression in tissues not previously linked to toxicities, suggesting the potential utilization of organ-specific NR interactions for therapeutic purposes.
... Decreased sensitivity of the receptor, which can be overcome with high concentrations of agonists, is commonly observed in variations within the LBD of nuclear receptors such as androgen receptor, MR, or vitamin D receptor. 37 Interestingly, UFC levels evolved as a mirror image of plasma ACTH levels in the case described herein. Currently, UFC above 150 µg/24 h is associated with a decrease in plasma ACTH levels, suggesting that endogenous hypercortisolism is sufficient to achieve effective negative feedback. ...
Objective
Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GRR569Q) in a patient with uncommon reversible glucocorticoid resistance syndrome.
Methods
We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation. We studied the impact of the variant on the tertiary structure of the ligand-binding domain through 3D modeling.
Results
The patient presented initially with an adrenal adenoma with mild autonomous cortisol secretion and undetectable adrenocorticotropin hormone (ACTH) levels. Six months after surgery, biological investigations showed elevated cortisol and ACTH (urinary free cortisol 114 µg/24 h, ACTH 10.9 pmol/L) without clinical symptoms, evoking glucocorticoid resistance syndrome. Functional characterization of the GRR569Q showed decreased expression of target genes (in response to 100 nM cortisol: SGK1 control +97% vs patient +20%, P < .0001) and impaired nuclear translocation in patient fibroblasts compared to control. Similar observations were made in transiently transfected cells, but higher cortisol concentrations overcame glucocorticoid resistance. GRR569Q showed lower ligand affinity (Kd GRWT: 1.73 nM vs GRR569Q: 4.61 nM). Tertiary structure modeling suggested a loss of hydrogen bonds between H3 and the H1–H3 loop.
Conclusion
This is the first description of a reversible glucocorticoid resistance syndrome with effective negative feedback on corticotroph cells regarding increased plasma cortisol concentrations due to the development of mild autonomous cortisol secretion.
... A subset of genes had higher differential expression in 45,X clusters compared to 46,XX clusters, particularly within somatic cell populations. These genes were in pathways that were enriched for functions related to cell death and apoptosis, including DUSP1, a driver of apoptosis within granulosa cells ; and NR4A1 (also known as (Achermann et al., 2017). Interestingly, anti-apoptotic markers were also . ...
Study question: Can single-nuclei and bulk RNA sequencing technologies be used to elucidate novel mechanisms of ovarian insufficiency in Turner Syndrome (TS)?
Summary answer: Using single-nucleus and bulk RNA sequencing approaches, we identified novel potential pathogenic mechanisms underlying ovarian insufficiency in TS including and beyond X chromosome haploinsufficiency.
What is known already: Turner syndrome (TS) is the most common genetic cause of Primary Ovarian Insufficiency (POI) in humans. Morphological analyses of human fetal 45,X ovaries have demonstrated fewer germ cells and marked apoptosis established by 15-20 weeks post conception (wpc); however, we do not understand why POI develops mechanistically in the first instance.
Study design, size, duration: Single-nucleus RNA sequencing (snRNA-seq): two 46,XX and two 45,X (TS) human fetal ovaries at 12-13 wpc. Bulk RNA sequencing: 19 human fetal ovary, 20 fetal testis, and 8 fetal control tissue (n=47 total samples; Carnegie Stage 22-16wpc).
Participants/materials, setting, methods: To identify novel potential mechanisms of ovarian insufficiency in TS and to characterise X chromosome gene expression in the 45,X ovary, we performed snRNA-seq of peri-meiotic 46,XX (n=2) and 45,X (n=2) fetal ovaries at 12-13 weeks post conception (wpc); and 2) a bulk RNA sequencing time-series analysis of fetal ovary, testis, and control samples across four developmental timepoints.
Main results and the role of chance: Germ and somatic cell subpopulations were mostly shared across 46,XX and 45,X ovaries, aside from a 46XX-specific/45,X-depleted cluster of oogonia (synaptic oogonia) containing genes with functions relating to sex chromosome synapsis; histone modification; intracellular protein regulation and chaperone systems. snRNA-seq enabled accurate cell counting localised to individual cell clusters; the 45,X ovary has fewer germ cells than the 46,XX ovary in every germ cell subpopulation, confirmed by histopathological analysis. The normal sequence of X-chromosome inactivation and reactivation is disrupted in 45,X ovaries; XIST was not expressed in 45,X somatic cells but was present in germ cell clusters, albeit with lower expression than in corresponding 46,XX clusters. The 45,X ovary has a globally abnormal transcriptome, with low expression of genes with proteostasis functions (RSP4X); cell cycle progression (BUB1B); and OXPHOS mitochondrial energy production (COX6C, ATP11C). Genes with higher expression in 45,X cell populations were enriched for apoptotic functions (e.g., NR4A1).
Limitations, reasons for caution: Limitations include the relatively small sample size of the snRNA-seq analysis and the focus on a fixed meiotic timepoint which may overlook a dynamic process over time.
Wider implications of the findings: We characterise the human fetal peri-meiotic 45,X ovary at single-cell resolution and offer insights into novel pathogenic mechanisms underlying ovarian insufficiency in TS. Although asynapsis due to X chromosome haploinsufficiency likely plays a significant role, these data suggest meiotic failure and ovarian insufficiency may be a combinatorial process characterised by periods of vulnerability throughout early 45,X germ cell development.
... Two key transcription factors (TFs) that regulate fetal adrenal development are the nuclear receptors NR0B1 (DAX-1) and NR5A1 (SF-1) (14,17,19,20,71). These genes encode 2 important nuclear receptors within a "core" set of 17 TFs identified, which were consistently differentially expressed in the adrenal cortex across time. ...
The adrenal glands synthesize and release essential steroid hormones such as cortisol and aldosterone, but many aspects of human adrenal gland development are not well understood. Here, we combined single-cell and bulk RNA sequencing, spatial transcriptomics, IHC, and micro-focus computed tomography to investigate key aspects of adrenal development in the first 20 weeks of gestation. We demonstrate rapid adrenal growth and vascularization, with more cell division in the outer definitive zone (DZ). Steroidogenic pathways favored androgen synthesis in the central fetal zone, but DZ capacity to synthesize cortisol and aldosterone developed with time. Core transcriptional regulators were identified, with localized expression of HOPX (also known as Hop homeobox/homeobox-only protein) in the DZ. Potential ligand-receptor interactions between mesenchyme and adrenal cortex were seen (e.g., RSPO3/LGR4). Growth-promoting imprinted genes were enriched in the developing cortex (e.g., IGF2, PEG3). These findings reveal aspects of human adrenal development and have clinical implications for understanding primary adrenal insufficiency and related postnatal adrenal disorders, such as adrenal tumor development, steroid disorders, and neonatal stress.
... FOXN3 interacts with Menin, the product of MEN1, which influences bone metabolism (Kaji, 2012). Nr2e3, as a nuclear receptor (Oh et al., 2008), is related to human disorders including reduced bone mineral density (Achermann and Jameson, 2003;Achermann et al., 2017). Overall, 25.3% of these UK Biobank (PIP ≥ 0.001) GWAS SNPs can be mapped; however, the majority of them (92.7%) are mapped to "desert" regions that are 250 kb away from the 200 BMD gene promoters, emphasizing the necessity for follow-up with 3D genome profiling assays such as pcHi-C (Mifsud et al., 2015) and its variants. ...
Motivation:
Elucidating functionally similar orthologous regulatory regions for human and model organism genomes is critical for exploiting model organism research and advancing our understanding of results from genome-wide association studies. Sequence conservation is the de facto approach for finding orthologous non-coding regions between human and model organism genomes. However, existing methods for mapping non-coding genomic regions across species are challenged by the multi-mapping, low precision, and low mapping rate issues.
Results:
We develop Adaptive liftOver (AdaLiftOver), a large-scale computational tool for identifying functionally similar orthologous non-coding regions across species. AdaLiftOver builds on the UCSC liftOver framework to extend the query regions and prioritizes the resulting candidate target regions based on the conservation of the epigenomic and the sequence grammar features. Evaluations of AdaLiftOver with multiple case studies, spanning both genomic intervals from epigenome datasets across a wide range of model organisms and GWAS SNPs yield AdaLiftOver as a versatile method for deriving hard-to-obtain human epigenome datasets as well as reliably identifying orthologous loci for GWAS SNPs.
Availability:
The R package AdaLiftOver is available from https://github.com/ThomasDCY/AdaLiftOver.
Supplementary information:
Supplementary data are available at Bioinformatics online.
... To date, defects in almost half of the 48 nuclear receptor genes have been involved in human disorders. 31 Both GOF and dominant-negative variants have been described in these disorders. [32][33][34][35][36][37] Interestingly, some of these variants act through similar mechanisms to those described here for RARB. ...
Purpose:
Dominant variants in the Retinoic Acid Receptor Beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.
Methods:
We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.
Results:
We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or co-activators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.
Conclusion:
Our study indicates that pathogenic variants in RARB are functionally heterogeneous and are associated with extensive clinical heterogeneity.
... Furthermore, as important intra-and intermolecular interactions have been reported in other nuclear receptors (e.g. RARβ 9 and GR 31 ), it will be of interest to investigate whether disease-causing mutations in nuclear receptors other than PPARγ have similar effects 32 . Based on the crystal structure, the R212Q mutation is expected to decrease the ability of the PPARγ hinge to engage in interactions within the minor groove of the DNA helix immediately 5' of the PPRE (referred to as the 5' extension or 5' upstream region; 5' UR) 11 . ...
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ’s ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.
... The nuclear receptor superfamily includes more than 40 transcriptional regulators that are activated or suppressed in response to ligand availability [1]. The interplay between nuclear receptors through a series of fine-tuned feedback mechanisms is pivotal in maintaining cellular and organ homeostasis as well as in the onset and progression of a number of diseases [2]. Nuclear receptor signaling is considered particularly relevant to liver homeostasis and pathophysiology [3]. ...
The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses. Furthermore, this review article provides an overview of the advances and the clinical development of FXR agonists in the treatment of liver diseases.
... NR5A1, also known as steroidogenic factor-1 (SF-1) is an orphan nuclear receptor transcription factor that plays a key role in many aspects of reproductive development and function (184). In 46,XY individuals the phenotypes associated with NR5A1 variants include a wide range of DSD conditions with or usually without adrenal insufficiency, including testicular dysgenesis with or without Müllerian structures, anomalies of androgen production, hypospadias, progressive androgenisation at puberty, and male infertility with normal genital development (185). In 46,XX individuals pathogenic variants are associated with primary ovarian insufficiency and early menopause (185). ...
... In 46,XY individuals the phenotypes associated with NR5A1 variants include a wide range of DSD conditions with or usually without adrenal insufficiency, including testicular dysgenesis with or without Müllerian structures, anomalies of androgen production, hypospadias, progressive androgenisation at puberty, and male infertility with normal genital development (185). In 46,XX individuals pathogenic variants are associated with primary ovarian insufficiency and early menopause (185). Recently the range of phenotypes associated with variant in NR5A1 has been extended to include 46,XX DSD. ...
... Recently the range of phenotypes associated with variant in NR5A1 has been extended to include 46,XX DSD. Amino acid variants of a specific arginine residue, p.Arg92, located in the highly conserved "A-box", which is required for appropriate DNA-binding, are associated with 46,XX ovotesticular DSD or testicular DSD (16,(184)(185)(186)(187)(188). To date, this phenotype has not been observed with missense variants elsewhere in the NR5A1 protein in 46,XX individuals. ...
DSD encompasses a wide range of pathologies that impact gonad formation, development and function in both 46,XX and 46,XY individuals. The majority of these conditions are considered to be monogenic, although the expression of the phenotype may be influenced by genetic modifiers. Although considered monogenic, establishing the genetic etiology in DSD has been difficult compared to other congenital disorders for a number of reasons including the absence of family cases for classical genetic association studies and the lack of evolutionary conservation of key genetic factors involved in gonad formation. In recent years, the widespread use of genomic sequencing technologies has resulted in multiple genes being identified and proposed as novel monogenic causes of 46,XX and/or 46,XY DSD. In this review, we will focus on the main genomic findings of recent years, which consists of new candidate genes or loci for DSD as well as new reproductive phenotypes associated with genes that are well established to cause DSD. For each gene or loci, we summarise the data that is currently available in favor of or against a role for these genes in DSD or the contribution of genomic variants within well-established genes to a new reproductive phenotype. Based on this analysis we propose a series of recommendations that should aid the interpretation of genomic data and ultimately help to improve the accuracy and yield genetic diagnosis of DSD.
