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.

Thyroid hormone (TH) regulates physiologic processes (e.g., skeletal growth, maturation of the CNS, heart rate and contractility, energy expenditure) via receptors (thyroid receptor α1 [TRα1], TRβ1, and TRβ2) encoded by separate genes (THRA/NR1A1, THBR/NR1A2), with differing tissue distributions: TRα1 is highly expressed in the CNS, myocardium, gastrointestinal tract, and skeletal muscle; TRβ1 is the predominant isoform in liver and kidney; TRβ2 expression is restricted principally to the hypothalamus, pituitary, retina, and inner ear. Such divergence of receptor subtype expression likely mediates distinctive phenotypes associated with defective THRB or THRA.

Resistance to THβ (RTHβ), usually dominantly inherited, is recognized by a characteristic biochemical signature of elevated circulating TH and non-suppressed thyroid-stimulating hormone levels, reflecting central (hypothalamic-pituitary) resistance to TH action, together with variable resistance in peripheral tissues. Approximately 160 different heterozygous THRB mutations, localizing to the ligand-binding domain (LBD) and involving both TRβ2 and TRβ1 isoforms, have been identified in the disorder (1).

Affected individuals may have nonspecific symptoms or a goiter, prompting thyroid function tests that suggest the diagnosis and are deemed to have generalized RTH (GRTH). In approximately 15% of cases, the same biochemical picture can be associated with thyrotoxic features (e.g., weight loss, tremor, anxiety, tachycardia in adults; failure to thrive and hyperkinetic behavior in children); a disproportionate resistance to TH in TRβ-expressing hypothalamus and pituitary (PRTH), with relative retention of hormone sensitivity in TRα-expressing peripheral tissues, may account for this phenotype. GRTH and PRTH phenotypes can be associated with the same TRβ mutation and may even coexist within a single family. Other recognized features of the disorder include attention-deficit hyperactivity disorder in childhood and dyslipidemia and reduced bone mineral density in adults (1).

Consonant with their location, most TRβ mutations impair hormone binding or (rarely) coactivator recruitment and inhibit 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 disorder, 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 acting TH analogue that lowers TH levels, can control thyrotoxic features of the disorder.

RTHα, characterized by features of hypothyroidism in selected tissues, eluded discovery probably because thyroid function tests are near-normal in the disorder. Most cases have been identified in childhood, with features including disproportionate (lower segment) growth retardation, macrocephaly, dysmorphic features, constipation, dyspraxia, and intellectual deficit. Biochemical abnormalities include low/low-normal thyroxine (T4) and high/high-normal triiodothyronine (T3) computing to a low T4/T3 ratio, variably reduced reverse T3, elevated muscle creatine kinase levels, and anemia (4, 5).

Heterozygous 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, Figure 3A, and ref. 5). Some THRA defects also involve the carboxyterminally 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 well-being.

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). (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.

The principal role of the vitamin D receptor (VDR, encoded by NR1I1) is in the regulation of calcium and phosphate metabolism with actions in the gastrointestinal tract, kidney, and bone. Hypocalcemia and associated symptoms (skeletal and respiratory muscle weakness, seizures) in the early neonatal period or infancy due to lack of VDR-dependent intestinal calcium absorption dominates the phenotype of autosomal recessive hereditary vitamin D–resistant rickets (HVDRR, also known as vitamin D–dependent rickets type II). Rickets manifests with bone pain, growth restriction, and fractures. Low circulating calcium and phosphate levels and raised alkaline phosphatase are associated with normal serum 25-hydroxy but very elevated 1,25 dihydroxyvitamin D3 (calcitriol) levels, secondary hyperparathyroidism, and elevated parathyroid hormone levels. Alopecia (patchy or total) affecting both scalp and body is a distinctive, non-osseous feature of the disorder.

Approximately 100 cases of HVDRR harboring approximately 45 different homozygous or compound heterozygous VDR mutations have been recorded: frameshift, premature-stop, and DNA-binding domain (DBD) mutations lead to complete loss of function. Additionally, approximately 20 LBD variants exhibit reduced ligand binding, failure to heterodimerize with retinoid X receptor (RXR), or selective loss of coactivator recruitment (Figure 3B); a single HVDRR case lacking a VDR mutation has also been described (7). In one family, a missense VDR mutation (p. Glu420Ala), which abolished coactivator binding and exhibited dominant-negative activity, mediated HVDRR in the heterozygous state (8). Patients with HVDRR require oral or intravenous calcium therapy; high-dose vitamin D or calcitriol treatment can overcome the receptor defect in LBD mutation cases (7), raising the possibility of structure-guided design of synthetic analogues for treatment of a subset of HVDRR (9).

Interestingly, alopecia occurs in patients with VDR mutations that lead to loss of receptor expression, DNA binding, or dimerization, but it is not a feature in cases with ligand binding or coactivator recruitment defects. This abnormality is unresponsive to calcitriol therapy, leading to the hypothesis that inhibition of target genes by unliganded, wild-type VDR maintains normal cycling of hair follicles, with loss of such repression mediating hair loss (Figure 2C). Supporting this notion, mutations in hairless, a known component of NR repression complexes, also cause an alopecia syndrome (atrichia with papules) (10).

Disruption of glucocorticoid receptor α (GRα, encoded by NR3C1) is associated with familial glucocorticoid resistance (FGR, also known as generalized glucocorticoid resistance or Chrousos syndrome) (11, 12). This can be dominantly or recessively inherited, with a range of features depending on the severity of the defect or underlying molecular mechanism. Individuals with FGR often present with fatigue, but other signs of glucocorticoid insufficiency are rare. Because of reduced central feedback, adrenocorticotropic hormone (ACTH) is elevated, increasing cortisol and partly compensating for glucocorticoid resistance. One consequence of elevated ACTH is an increase in adrenal mineralocorticoid and androgen production. Consequently, clinical and biochemical features of FGR can include hypertension, hypokalemia, and metabolic alkalosis as well as hirsutism, acne, male pattern baldness, oligomenorrhea, and infertility.

Most pathogenic missense variants in GRα are located in the LBD and affect glucocorticoid binding or transactivation. Patients or carriers with heterozygous changes tend to have a milder phenotype, although dominant-negative LBD variants have been reported (p.Ile559Asn, Ile747Met) (13, 14). LBD mutants often show variably reduced ligand binding affinity as well as delayed nuclear translocation and altered interactions with coactivators (e.g., p160) (14). Clinical and biochemical features in individuals with homozygous mutations in NR3C1 are usually more severe. No familial activating mutations in GRα have been reported, but a heterozygous variant (p.Asp410His) was reported in a woman with features of tissue-selective glucocorticoid hypersensitivity (e.g., visceral obesity, dyslipidemia, type 2 diabetes [T2D], hypertension) (15). This mutant receptor increased transactivation of glucocorticoid-responsive genes.

The mineralocorticoid receptor (MR, encoded by NR3C2) plays a key role in renal sodium retention and cardiovascular endocrinology. Pathogenic loss-of-function variants in this receptor are associated with a renal form of mineralocorticoid resistance known as autosomal-dominant (or sporadic) pseudohypoaldosteronism type 1 (PHA I) (16, 17). Children typically present in early infancy with dehydration and failure to thrive and have hyponatremia, hyperkalemia, and elevated aldosterone levels and plasma renin activity (PRA). Some infants with elevated aldosterone and PRA are asymptomatic. Sodium supplementation is usually required, but the condition improves in childhood. In contrast, the autosomal recessive form of PHA I, due to defects in the amiloride-sensitive epithelial sodium channel, is a more severe systemic condition that does not remit with age.

Pathogenic MR mutations include nonsense, frameshift, splice and missense mutations, with a potential hotspot at c.2839C>T (p.Arg947*). Missense mutations often affect key amino acids in the LBD and impair aldosterone binding and aldosterone-dependent transactivation (16, 18). Nuclear localization can sometimes be affected and different variants may have differential effects on MR-target genes (e.g., SGK1, NDRG2, GILZ, SCNN1A) (18, 19).

A gain-of-function MR variant was reported in 2000, in one family with early-onset hypertension (onset before the age of 20) (20). Females also exhibited marked hypertension during pregnancy. The heterozygous p.Ser810Leu variant identified in affected family members showed mild constitutive activity together with inappropriate responsiveness to progesterone. The leucine substitution at position 810 increases van der Waals interactions and lessens hydrogen bonding with steroid side groups, thereby enabling progesterone to bind and activate mutant MR (Figure 3C). Although this germline mutation is rare, it exemplifies how genetic variants in NRs can potentially alter ligand specificity; such altered ligand specificity is well recognized with somatic ERα variants in breast cancer or androgen receptor (AR) mutations in prostate cancer.

Estrogen receptor α (ERα, encoded by ESR1 [also referred to as NR3A1]) is one of the best-studied NRs in human biology. To date, only three genomic pathogenic variants associated with a clear phenotype have been reported; however, these cases do provide important insight into the role of ERα in human development and health.

The first report of a pathogenic ESR1 variant in 1994 involved a 28-year-old man who presented with tall stature (204 cm), prolonged linear growth, delayed epiphyseal fusion, and reduced bone mineral density (z score –3.1) (21, 22). He had normal puberty, but had elevated levels of follicle-stimulating hormone and luteinizing hormone and reduced sperm viability. He also had impaired glucose tolerance, hyperinsulinemia, and an abnormal lipid profile with evidence of early coronary atherosclerosis, although his BMI was elevated (30.5 kg/m²). Genetic analysis revealed a homozygous stop gain variant (p.Arg157*). He had mildly elevated serum estradiol and resistance to estrogen treatment.

In 2013, the first female with estrogen resistance was reported (23). This 18-year-old woman presented with absent breast development, primary amenorrhea, and abdominal pain due to hemorrhagic ovarian cysts. She had a small uterus with no endometrium, but did have evidence of androgenization. Her bone age was markedly delayed (>4 years), she did not have a pubertal growth spurt, and her bone density was reduced (z score –2.4) with elevated markers of osteoblastic activity. Her estradiol was very elevated (10-fold above normal) with elevated inhibin A and mildly raised gonadotropins, and she was resistant to estrogen treatment. Analysis of ESR1 revealed a homozygous missense variant (p.Gln375His) in the LBD that impaired estrogen responsiveness in cell-based assays. More recently, a description was published of the first known family with estrogen resistance (p.Arg394His) (24).

These reports provide important information about the role of ERα in humans. As expected, ERα mediates the main effects of estrogen on bone growth and mineralization, as well as breast and uterine development in females. As in ER-knockout mice, gonadotropin concentrations are higher in males, possibly because very high estradiol and inhibin A levels in females partly mediate central feedback. Finally, the woman described above had no evidence of hyperinsulinemia or glucose intolerance, but she had a low BMI (16.6 kg/m2) and body fat (28%). Long-term monitoring is needed to see whether metabolic abnormalities develop, although the difference in BMI between the two individuals may be a factor influencing insulin sensitivity.

Disruption of the AR (encoded by NR3C4) results in androgen insensitivity syndrome (AIS) (25). This X-linked condition was first reported in 1953 and has historically been called “testicular feminization syndrome” (26). Women with complete AIS (CAIS) typically present during late adolescence with primary amenorrhea. Subsequent investigations show an absent uterus, 46,XY karyotype, and elevated testosterone concentrations. Breast development usually occurs in adolescence due to the aromatization of androgens to estrogens, but androgen-dependent pubic hair is often absent or sparse. Occasionally the diagnosis is made when testes are found during hernia repair in childhood or with karyotype analysis for another indication. As with most conditions, a spectrum of phenotypes can occur. Partial AIS (PAIS) typically presents with atypical genitalia or hypospadias in the newborn period, and gynecomastia is a common feature at adolescence in boys with this condition (27). Mild AIS (MAIS) has also been reported in men with oligospermic infertility (28).

More than 800 different pathogenic variants in the AR have been reported. These changes include stop-gain, frameshift, and missense variants that are distributed throughout the gene and have been reviewed extensively elsewhere (26, 29, 30). Missense variants tend to affect important amino acids involved in DNA binding or ligand interactions, but many different residues can be affected. Although some mutations associate more with complete or partial phenotypes, there can be overlap between the type and location of the change, its activity in in vitro assays, and the degree of androgen insensitivity in affected individuals. Missense mutations in the hydrophobic ligand-binding pocket of the LBD usually cause CAIS (26), while missense mutations in the large aminoterminal activation function domain (AF-1) usually cause PAIS or MAIS. Of note, a subset of individuals thought to have AIS do not have variants in the AR gene, even though cultured genital fibroblasts show androgen resistance in vitro (e.g., reduced dihydrotestosterone-induced apolipoprotein D expression) (31). Disruption of AR-dependent cofactors or post-receptor signaling mechanisms have been proposed as the cause (AIS type II) (31).

The AR is unusual in that it has a variable number of polyglutamine and polyglycine repeats in the aminoterminal region of the receptor. Expansion of the polyglutamine tract (to 38–65 CAG trinucleotide repeats) is associated with X-linked spinal and bulbar muscular atrophy (SBMA, also known as Kennedy disease) (32). This condition results from AR-polyglutamine toxicity; the mutant protein misfolds and aggregates in spinal cord motor neurons and muscle cells. SBMA can sometimes be associated with reduced androgen action, gynecomastia, low sperm count, and testicular atrophy (33).

Steroidogenic factor-1 (SF-1, encoded by NR5A1) was identified following the search for a common regulator of steroidogenic enzyme transcription (34, 35). Complete deletion of Nr5a1 in the mouse resulted in adrenal agenesis, gonadal (testicular) dysgenesis with persistent Müllerian structures (in the uterus and upper vagina) in XY animals and variable defects in gonadotropin release, confirming SF-1 as a key player in adrenal and gonad biology (36). Subsequently, other metabolic features such as late-onset obesity and ventromedial hypothalamic abnormalities were reported (37, 38).

The first descriptions of pathogenic loss-of-function variants in NR5A1 in humans were published in 1999 and 2002 (39, 40). These reports included two 46,XY girls with testicular dysgenesis, Müllerian structures, and salt-losing primary adrenal insufficiency. The first child had a de novo heterozygous change (p. Gly35Glu) in the P-box region of the SF-1 DBD that affected binding to and transcriptional activation of target gene response elements (39). Functional studies suggested this was largely a gene dosage–dependent competitive effect, although partial dominant negativity was reported in some systems. The second child had a homozygous pathogenic change (p. Arg92Gln) affecting the A-box region of SF-1 DBD (40). SF-1 belongs to a small subgroup of NRs that bind to DNA as monomers rather than as homo- or heterodimers. The A-box region is involved in stabilizing monomeric binding through an interaction with the DNA minor groove. Thus, a heterozygous P-box change and homozygous A-box change may have similar phenotypes.

The past decade has seen great increases in the number of reported pathogenic changes in NR5A1 and also the spectrum of SF-1–associated conditions (41). More than 200 individuals and families are now described in the literature. Heterozygous loss-of-function variants in NR5A1 occur in approximately 15% of individuals with testicular dysgenesis and reduced androgen production, resulting in 46,XY differences in/disorders of sex development (DSDs) (42). Phenotypes can range from females with a 46,XY karyotype to boys with penoscrotal hypospadias or undescended testes. Milder variants in NR5A1 can be associated with a small subset of male factor infertility, sometimes with progressive endocrine dysfunction (43). Variants in NR5A1 are also associated with primary ovarian insufficiency (POI) in 46,XX women, although the age of onset and natural time course are highly variable (44). Although many variants occur de novo, around 30% can be carried and maternally transmitted as a sex-limited dominant trait. Because multiple members of a family may have 46,XY DSD with 46,XX females being at risk of POI, careful family history and counseling is important. Very rarely, mutations in NR5A1 can cause primary adrenal insufficiency in 46,XX girls.

Although true gain-of-function variants in SF-1 have not been reported, recent observations suggest that recurrent, heterozygous missense changes in codon 92 (p.Arg92Trp, p.Arg92Gln) of NR5A1 are associated with ovotestes or testes in individuals with a 46,XX karyotype (45). Several individuals or families of diverse genetic ancestry have been reported. This particular amino acid change may interfere with expression of DAX-1 (dosage-sensitive sex reversal–adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1; see below) through WNT signaling in the developing gonad, but the exact mechanism that “switches” the ovary into a testis remains unclear (Figure 3D).

DAX-1 (encoded by NR0B1) is an orphan NR that lacks the typical NR DBD but that has an aminoterminal region motif comprising three 66–67 amino acid tandem repeats. Similar to SF-1, DAX-1 plays a key role in adrenal and reproductive development.

DAX-1 disruption was first reported to cause X-linked AHC in 1994 (46, 47). Since then, more than 200 individuals or families have been reported to have pathogenic variants in NR0B1 (41). The classic features in males include primary adrenal insufficiency in early infancy or childhood, delayed or arrested puberty due to disordered gonadotropin release, and impaired spermatogenesis.

Nonsense or frameshift variants in NR0B1 occur throughout the gene, whereas pathogenic missense variants tend to cluster in key areas of the ligand-like binding domain in regions that form the hydrophobic core of the protein (48). Few missense changes in the aminoterminal repeat structure of DAX-1 have been reported. Partial loss-of-function missense variants can be associated with a milder phenotype of delayed onset adrenal insufficiency in early adulthood, or partial hypogonadotropic hypogonadism (49). Surprisingly, milder phenotypes can also occur due to stop gain variants at the start of the protein (p. Trp37*, p.Trp39*); this effect is likely due to re-initiation of translation of a truncated DAX-1 protein from a downstream methionine at codon 83 that remains partially functional (due to the repeat motif structure) and “rescues” the phenotype (50).

Although DAX-1–associated conditions are well established, the exact biological role of DAX-1 remains unclear. Many studies demonstrate that DAX-1 acts as a transcriptional repressor, potentially through a direct interaction with SF-1 (48). Indeed, duplication of the locus containing DAX-1 is associated with testicular dysgenesis, suggesting that it may act as an “anti-testis” gene. DAX-1 may play a role in regulating progenitor cell differentiation. Loss of DAX-1–dependent repression may result in premature differentiation of progenitor cells without appropriate expansion of cell numbers, ultimately resulting in tissue hypoplasia. Indeed, loss of DAX-1 can sometimes be associated with early puberty in humans, and transient adrenal hyperresponsiveness has been reported in Dax1 knockout mice (51). Whether these phenomena reflect the true biological basis of DAX-1 function is still unclear.

Retinoic acid receptor-β (RARB, encoded by NR1B2) is expressed in many tissues during development, and deletion of Nr1b2 in mice causes multiple defects (e.g., CNS, vision, hearing, musculoskeletal, cardiovascular, gastrointestinal, pulmonary, renal) and high lethality.

In 2013, the first pathogenic RARB variants were reported in patients with STRA6 mutation-negative syndromic microphthalmia and additional features such as pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defects (PDAC syndrome). In one family, two siblings were found to be compound heterozygous for disruptive variants (p.Arg119*/p.Ile403SerfsTer15) (52). At least three other unrelated children with microphthalmia and one or more of these additional features have been found to carry de novo heterozygous changes affecting an arginine hotspot at codon 387 (e.g., p.Arg387Ser, p.Arg387Cys), potentially mediating a gain-of-function mechanism (52, 53). Taken together, these findings provide support for retinoic acid pathways in human eye development and organogenesis. Indeed, NR1B2 is highly expressed in the human retina, unlike NR1B1 or NR1B3 (54).

RAR-related orphan receptor γ (RORγ, encoded by RORC [also known as NR1F3]) plays a key role in thymocyte development and function, including differentiation of the Th17 cell subset. Recently, homozygous pathogenic variants in RORC, causing disruption of both the ROR-γ and ROR-γ–t isoforms, have been reported in seven individuals from three unrelated consanguineous pedigrees with immunodeficiency (55). These families — from Palestine, Chile, and Saudi Arabia — have evidence of chronic mucocutaneous candidiasis (due to IL-17A and IL-17F deficiency) combined with susceptibility to mycobacterial disease and disseminated infections following Bacillus Calmette-Guérin vaccines. Patients also all had a small thymus.

Photoreceptor-specific NR (PNR, encoded by NR2E3) is involved in retinal photoreceptor cell differentiation and degeneration, and its disruption results in retinal degeneration in the rd7 mouse. Pathogenic variants in NR2E3 cause enhanced S-cone syndrome (ESCS) (56), an inherited retinal disorder characterized by increased visual function of the minority S (blue) cones and decreased L/M (red/green) cone and rod function. These findings likely represent increased S-cone proliferation at the expense of other cell types during cell fate determination. Patients typically develop night blindness and evidence of retinitis pigmentosa (RP). Autopsy studies have shown absence of rods and retinal disorganization and degeneration (57).

Among pathogenic variants in NR2E3 reported to cause ESCS, homozygous p.Arg311Gln variants are most common and represent a hotspot for disease among the Crypto-Jewish population in Portugal (58). The same change is also associated with Golgmann-Favre syndrome, a more severe form of ESCS (55). Variants in NR2E3 are also found in autosomal-recessive and -dominant forms of RP (59, 60). Approximately 3% of dominantly inherited RP is due to a heterozygous PNR mutation (p.Gly56Arg) in the first zinc finger of the DBD, exhibiting dominant-negative activity (60, 61). Other variants cause altered cellular localization or homo- or hetero-dimerization with TLX/NR2E1 and RXRα/NR2C1 (62, 63). Another NR, Rev-erb-α/NR1D1, has been used to potentially “rescue” disease progression in the rd7 mouse (64).

Chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) is widely expressed in many tissues. It is strongly expressed in the brain and peripheral nervous system and has a potential role in regionalization of the neocortex and axonal projection. In humans, NR2F1 haploinsufficiency and de novo heterozygous mutations in NR2F1 have been reported in patients with Bosch-Boonstra-Schaaf optic atrophy syndrome (65, 66). Additional characteristics include developmental delay and variable, nonspecific facial features. Most missense mutations (such as p.Arg112Lys, p.Ser113Arg, and p.Arg115Pro) cluster in the DBD and may be associated with a more severe phenotype (66, 67). Other features reported recently include hypotonia, oromotor dysfunction, thinning of the corpus callosum, seizures, autism spectrum disorder, and hearing impairment (67).

COUP-TFII (encoded by NR2F2) plays a role in angiogenesis, vascular remodeling, and heart development as well as in more widespread regulation of cell fate during embryonic development. Recently, heterozygous variants in NR2F2 have been reported in patients with a range of congenital cardiac disease phenotypes (68). In one family, a 3-bp duplication in NR2F2 segregated with multiple cardiac defects (i.e., atrioventricular septal defect [AVSD], aortic stenosis/VSD, and tetralogy of Fallot), whereas other heterozygous missense mutations or deletions of NR2F2 have been associated with AVSD, hypoplastic left heart syndrome, or aortic coarctation (68). Congenital diaphragmatic hernia may be an association in mice and humans (69).

Rev-erb-β (encoded by NR1D2) has several proposed actions including being a potential repressor of gene transcription. Recently, a de novo heterozygous mutation in NR1D2 was found in one individual with congenital heart disease (AVSD) (70). This variant (p.Arg175Trp) affects binding to the DNA minor groove and impairs transcriptional repression (70). Detailed analysis of Nr1d2^–/– mice indicated a similar phenotype (70). As this is a very recent observation, the true contribution of Rev-erb-β to developmental heart defects is not yet known.

Estrogen-related receptor β (ERRβ, encoded by NR3B2) has structural homology to the ERs and binds ER response elements but is not activated by estrogens. ERRβ plays a role in placental development and is expressed in several tissues such as the inner ear during development and postnatal life (71). Homozygous disruption of ESRRB was first reported in a large consanguineous Turkish family with autosomal-recessive nonsyndromic hearing loss (type 35) (72). Homozygous point mutations in the DBD and, more often, in the “ligand”-binding domain of ERRβ have also been reported as a rare cause of nonsyndromic hearing loss, often in consanguineous families (72). A potential link between disruption of ESRRB and dental caries has also been proposed (73).

Farnesoid X receptor (FXR, encoded by NR1H4), a bile acid–activated NR, is a key mediator of bile acid homeostasis, regulating target genes that mediate hepatic export (e.g., bile salt export pump [ABCB11], multidrug resistance protein 3 [ABCB4]), biosynthesis (e.g., CYP7A), or enterohepatic circulation (e.g., NTCP, IBABP) of bile acids, limiting their intrinsic hepatocellular toxicity.

Four different heterozygous NR1H4 variants (–1G>T, p.Met1Val, p.Trp80Arg, and p.Met173Thr) that reduce its expression or transcriptional activity were identified by screening 92 women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterized by late gestational pruritus and abnormal maternal and fetal liver function, predisposing to fetal distress and prematurity (74). The heterozygous –1G>T variant was subsequently identified in an unrelated ICP case (75).

Progressive familial intrahepatic cholestasis (PFIC) comprises three subtypes known to be associated with mutations in transport proteins (PFIC-1, encoded by ATP8B1; PFIC-2, encoded by ABCB11/BSEP; and PFIC-3, encoded by ABCB4), but 30% of cases are idiopathic. FXR variants have recently been identified in four children with severe neonatal cholestasis that progressed to liver failure that was terminal or required transplantation. A homozygous premature stop mutation (p.Arg176*) abrogating DNA binding and function was identified in one family, and compound heterozygosity for an in-frame DBD insertion (pTyr139_Asn140insLys) plus a 31-kb deletion encompassing the first two coding exons of NR1H4 was identified in a second family. Similar to previous PFIC cases with defective bile salt export pump (BSEP, a known FXR target), cholestasis was associated with low/normal γ-glutamyl transferase levels and reduced BSEP expression. Severe vitamin K–independent coagulopathy, attributed to reduced FXR-dependent clotting factor levels and reduced circulating levels of other FXR-dependent hormones and metabolites, may represent other distinctive, diagnostically useful biomarkers (76).

Hepatocyte nuclear factor 4α (HNF4α, encoded by NR2A1) controls gene expression in the liver (approximately 40% of actively transcribed genes) and pancreas (11% of islet cell genes) and regulates pathways of hepatic gluconeogenesis and pancreatic insulin secretion (77).

Maturity-onset diabetes of the young (MODY), usually defined as diabetes mellitus (diagnosed before age 25 years) with negative islet cell autoantibodies, is most commonly (in about 50% of cases) due to mutations in HNF1α (MODY type 3), a homeobox family transcription factor, with HNF4A variants accounting for a further 10% of cases (MODY type 1). Approximately 100 different heterozygous mutations (58% missense, 20% frameshift or premature stop, 5% splice site) localizing to HNF4A coding exons have been recorded in this dominantly inherited disorder; a further 5% of variants localize to the pancreatic P2 promoter region of HNF4A, disrupting known tissue-specific transcription factor binding sites (77). Some HNF4α mutations, even those located outside the canonical DBD, compromise a protein interface in the HNF4α homodimer bound to DNA (78), with other variants disrupting transactivation, nuclear localization, or protein stability. Due to the large number of HNF4α-regulated target genes in liver and pancreas, it has been postulated that haploinsufficiency, with loss of even a fraction of functional receptor homodimers, reduces pancreatic glucose-dependent insulin secretion, mediating MODY (79).

In addition to a young age of diagnosis and family history of early-onset diabetes, reduced serum ApoA2 (known to be HNF4α regulated) and triglyceride levels and exquisite sensitivity to sulfonylurea drug therapy may be useful markers of HNF4α MODY (80). HNF4A mutation carriage is also associated with excess insulin secretion, resulting in macrosomia and neonatal hyperinsulinemic hypoglycemia (HH) in up to 50% of babies; the latter mandates neonatal surveillance of affected pregnancies because HH can be either mild and transient or more severe, requiring treatment with diazoxide (81). In addition to neonatal hyperinsulinism and macrosomia, renal proximal tubulopathy (Fanconi syndrome) with elevated urinary calcium, phosphate, and oxalate causing nephrocalcinosis has been recorded in patients with a specific HNF4α mutation (p.Arg76Trp) (82).

GWAS do show linkage of common variants around the HNF4A locus with T2D; a rare variant (p.Thr130Ile) in HNF4A confers a modest (1.2-fold) risk of T2D and is positively associated with HDL cholesterol levels (77).

PPARγ (encoded by NR1C3) is essential for adipocyte differentiation but also regulates target genes that mediate triglyceride hydrolysis and fatty acid and glycerol uptake, together with genes involved in fatty acid re-esterification and lipid storage (83). Heterozygous, missense PPARG mutations (p. Pro467Leu, Val290Met), impairing its ligand-dependent transcriptional activity, were first identified in patients with severe insulin resistance (IR) and early-onset T2D (84); subsequently, the phenotype was recognized to encompass a distinctive pattern of partial lipodystrophy. Additional features, such as hepatic steatosis and dyslipidemia, likely reflect an impaired ability to buffer dietary lipid load, with tissue lipotoxicity mediating IR. The resulting hyperinsulinemia mediates polycystic ovarian dysfunction and acanthosis nigricans. Hypertension that occurs independent of diabetic comorbidities is also a feature, suggesting a direct role for PPARγ in control of vascular tone (83).

Rare heterozygous PPARG variants associated with lipodystrophic IR localize to the LBD or DBD, disrupting either DNA binding or ligand-dependent transcription activation functions. Additionally, mutant receptors inhibit function of their wild-type counterparts in a dominant-negative manner (85). In a large, digenic kindred, PPARγ haploinsufficiency alone did not mediate IR, but acted in concert with a PPP1R3A mutation that affects muscle glycogen synthesis (86). Whole exome sequencing of around 9,000 individuals with T2D identified nine functionally deleterious, rare PPARG variants that confer substantial disease risk; however, it could not be ascertained whether adipose mass was reduced in these subjects (87). A common PPARG variant (p.Pro12Ala) that occurs with varying frequency (2% to 18%) in different ethnic groups is associated with a reduction in T2D risk (odds ratio 0.86). Conversely, the Pro12 allele is present in 80% of humans and can increase population T2D risk by up to 25% (85). Reduced target gene activation and induction of adipogenesis by the Ala12 PPARγ variant may lower adipose mass and improve insulin sensitivity in carriers, being the basis of its protective effect (88). A rare variant (p.Pro113Gln) in the PPARγ aminoterminal domain that exhibits gain of transcriptional function has been documented in four obese but paradoxically diabetic German subjects, but this or similar variants have not been found in other obese populations, suggesting a strong founder effect (85).

Small heterodimer partner (SHP, encoded by NR0B2) is an atypical orphan NR that has a ligand-like binding domain with sequence homology to other NRs but with a truncated aminoterminal region that lacks a true DBD. Heterozygous NROB2 variants with a diminished ability to inhibit HNF4α function were reported in 7% of Japanese patients with early-onset T2D, mild/moderate obesity, and increased birth weight (89). A separate study documented loss-of-function NR0B2 variants in 2.4% (19/805) of Japanese people with T2D, but also found these variants in 0.8% (6/752) of controls without diabetes (90). In contrast, studies in different populations have not consistently found such high enrichment for rare SHP variants in cohorts with obesity or diabetes (81–94).

The identification of naturally occurring NR mutations over the last 30 years has provided insights into their structure and function, but there are still many NRs for which an associated disorder has not yet been discovered. Looking to the future, exome or genome sequencing may uncover an association of NR gene variants with unexpected phenotypes or disorders not readily predicted from their known roles in physiologic or developmental processes. In other situations, the phenotype might be subtle or even embryonic lethal. These technologies will also identify genetic variants whose functional consequences are uncertain, emphasizing the need to develop relevant, high-throughput assays of variant NR function that can accurately predict their pathogenic significance, as has been described recently for PPARG (95).

With disorders of many classical NRs associated with changes in hormone levels linked to their cognate ligands, it is likely that defects in orphan receptors are also accompanied by distinctive changes in circulating metabolites or proteins. Metabolomic or proteomic profiling of case cohorts with defined NR gene defects may discern characteristic biochemical signatures, enabling better diagnosis of associated disorders or providing clues to the identification of unknown orphan receptor ligands.

A subset of individuals with typical clinical or biochemical features suggestive of disordered NR action do not have mutations in NR proteins, and it is possible that variants in non-coding regions of the genome affecting function of enhancer regions or involving epigenetic modification of chromatin or non-coding RNAs account for such cases. Alternatively, it is possible that defects in genes encoding NR cofactor proteins may be associated with such phenotypes. With our increasing knowledge of the human genome and application of high-throughput technologies to genome analysis and small-molecule screening, the next 30 years are likely to be an equally exciting time for human NR research.

Our research is supported by funding from the Wellcome Trust (Investigator Award 095564/Z/11/Z to KC; Senior Research Fellowship in Clinical Science 098513/Z/12/Z to JCA; Investigator Award 100237/Z/12/Z to JS), the National Institute for Health Research Biomedical Research Centre at Cambridge (to KC), and Great Ormond St Hospital for Children NHS Foundation Trust and University College London (to JCA). JS is a Royal Society Wolfson Research Merit Award Holder.

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.

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information:J Clin Invest. 2017;127(4):1181–1192.https://doi.org/10.1172/JCI88892.

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