NR1H4 (nuclear receptor subfamily 1, group H, member 4)

	A. NR1H4 gene structure. Schematic representation of the NR1H4 gene into 11 exons showing the alternative splicing and the start triplets that generate the 4 known isoforms. These have been classified according to the difference in the initial region of mRNA (α1 and α2) and the presence (+) or absence (-) of a 12-bp insert in the exon 5. B. NCBI reference sequences for FXR variants and isoforms. Variants 1 and 6, and variants 2 and 5 encode the same isoforms.
Description	In humans, FXR is encoded by the NR1H4 gene, consisted of 11 exons and 10 introns.
Transcription	4 alternatively spliced transcript variants encoding different isoforms have been described for this gene. Variants 3 and 4 contain an alternate 5'-terminal exon resulting in isoforms FXRα2 longer than FXRα1, coding by variants 2 and 5, with a distinct N-terminus due to translation initiation from an alternate in-frame start codon in the exon 3. Use of an alternate in-frame donor splice site at exon 5 results in FXRα1(-) and FXRα2(-) variants that miss a 4 amino acid segment compared to FXRα1(+) and FXRα2(+) isoforms.
Pseudogene	A pseudogene of FXR has been located on chromosome 1 (1p13.1-1p13.3) (Pseudogene.org).

Note	FXR is a ligand-activated transcription factor belonging to the nuclear receptor superfamily.
	FXR isoforms. Schematic representation of FXR isoforms classified based on the presence of the exons 1 and 2 (FXRα1) or 3 (FXRα2) in the initial region of the mRNA and the presence (+) or the absence (-) of the amino acid sequence MYTG in exon 5. AF1 and AF2: ligand-independent and -dependent transactivation domains, respectively; DBD: DNA binding domain; H: hinge region; LBD: ligand binding domain.
Description	FXR shares the typical structure of other nuclear receptors, including the N-terminal DNA binding domain (DBD) and the C-terminal ligand binding domain (LBD) (Modica et al., 2010). DBD contains two zinc fingers motifs involved in DNA binding and dimerization with RXRα. Hinge region connects the DBD with the LBD, and contains the insert of the amino acid sequence MYTG in the FXRα1/2(+) isoforms. Ligand-independent (AF-1) and -dependent (AF-2) transactivation domains involved in the interaction with co-repressors and co-activators are located in N- and C-termini, respectively.
Expression	FXR is expressed at high levels in the liver, small intestine, kidney and adrenal gland (Huber et al., 2002). Lower FXR levels can be detected in other organs forming the gastrointestinal tract, pancreas, breast and endothelial cells. The liver predominantly expresses FXRα1(+/-), whereas FXRα2(+/-) are the most abundant isoforms in kidney and intestine. In all cases, the proportion of FXRα(1/2)(+) and FXRα(1/2)(-) isoforms is approximately 50% (Vaquero et al., 2013b).
Localisation	When activated FXR translocates to the nucleus.
Function	Binding of bile acids, the natural ligands of FXR, to the receptor leads its translocation to the cell nucleus, formation of a heterodimer RXRα and binding to FXR response elements on DNA, which activates the transcription of its target genes. Among FXR target genes are those encoding most of the proteins involved in bile acid metabolism and transport (Modica et al., 2010). Additional target genes have recently been described to be involved in FXR-mediated regulation of several body functions, such as prevention of hepatic and intestinal carcinogenesis, liver regeneration, intestinal barrier, attenuation of adverse effects of cholestasis, prevention of gallstone formation, and chemoprotection (Vaquero et al., 2013a). Some of the effects of FXR are mediated by the induction of the small heterodimer partner (SHP), a negative regulator encoded by the NR0B2 gene. This transcription factor interacts with other nuclear receptors blocking its activation. Glucocorticoids are able to directly activate FXR but they also antagonize the expression of FXR and its target genes (Rosales et al., 2013).
Homology	DBD domain is a highly conserved domain, whereas LBD domain is moderately conserved in sequence and highly conserved in structure between the various nuclear receptors (Modica et al., 2010). According to sequence homology NR1H4 has been included into the liver-X-receptor-like group of genes belonging to the thyroid hormone receptor-like subfamily of nuclear receptors, together with NR1H2 (liver X receptor-β) and NR1H3 (liver X receptor-α).

Note	The presence of missense mutations in the NR1H4 gene is unusual, suggesting an important role of this gene in the maintenance of organ function and cellular homeostasis.
	Definition, nomenclature, and allelic frequency of clinically relevant NR1H4 genetic variants. MAF refers to the frequency at which the less common allele occurs in a given population according to the NCBI SNP database. Nucleotide positions refer to the ORF of the NM_005123 sequence. Amino acid positions refer to the NP_005114 (FXRα1(-)) or NP_001193921 (FXRα2(-)) proteins. AF-1, ligand-independent transactivation domain.
Somatic	c.-1G>T is a common variation resulting in reduced translation efficiency (Marzolini et al., 2007) that might predispose to inflammatory bowel diseases (Attinkara et al., 2012) and intrahepatic cholestasis of pregnancy (Van Mil et al., 2007). c.-189-1174G>A and c.-190+7064C>T are intronic SNP that have been associated with an altered glucose and lipid metabolism (Heni et al., 2013). c.1A>G and c.518T>C are two rare mutations in the coding sequence of FXR whose consequence is a reduction of the function of the protein. Both predispose to intrahepatic cholestasis of pregnancy (Van Mil et al., 2007).

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