Alternative titles; symbols
HGNC Approved Gene Symbol: SREBF1
SNOMEDCT: 403442005;
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38): 17:17,811,334-17,836,986 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p11.2 | Ichthyosis, follicular, with atrichia and photophobia syndrome 2 | 619016 | Autosomal dominant | 3 |
| Mucoepithelial dysplasia, hereditary | 158310 | Autosomal dominant | 3 |
Sterol regulatory element-binding protein-1 (SREBP1) and SREBP2 (600481) are structurally related proteins that control cholesterol homeostasis by stimulating transcription of sterol-regulated genes (summary by Osborne, 2001).
Sterol regulatory element-1 (SRE1), a decamer (5-prime-ATC-ACCCCAC-3-prime) flanking the low density lipoprotein receptor gene (LDLR; 606945), activates transcription in sterol-depleted cells and is silenced by sterols. Yokoyama et al. (1993) cloned the cDNA corresponding to human SREBP1, a protein that binds SRE1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism. SREBP1 contains a basic helix-loop-helix leucine zipper (bHLH-ZIP) motif, but it differs from other bHLH-ZIP proteins in its larger size (1,147 amino acids) and target sequence. Instead of an inverted repeat (CANNTG), the target for all known bHLH-ZIP proteins, SRE1 contains a direct repeat of CAC.
Hua et al. (1995) described the cloning and characterization of SREBP1 from a human cosmid DNA library. Alternative splicing at both the 5-prime and 3-prime ends of the mRNA results in several forms of the protein whose functional differences were unknown.
Shimomura et al. (1997) noted that the 5-prime end of SREBP1 exists in 2 forms, designated 1a and 1c, resulting from the use of 2 transcription start sites that produce 2 separate 5-prime exons, each of which is spliced to a common exon 2. Among organs in adult mice, the authors found that expression of the 1a and 1c transcripts varied; the 1a exon predominated in cells that differentiated into adipocytes and in the spleen, whereas the 1c exon predominated in liver cells, white and brown adipose tissue, adrenal gland, and several other tissues of the adult mouse. The findings suggested that the 2 transcripts are controlled independently in specific organs in response to metabolic factors.
Hua et al. (1995) determined that the SREBF1 gene is 26 kb long and has 22 exons and 20 introns.
Najafi-Shoushtari et al. (2010) identified the miR33B gene in intron 17 of the SREBP1 gene. The presence of this microRNA in SREBP1 is not conserved in mice.
By analysis of human/rodent somatic cell hybrids and fluorescence in situ hybridization, Hua et al. (1995) mapped the SREBF1 gene to chromosome 17p11.2.
Yokoyama et al. (1993) found that overexpression of SREBP1 activates transcription of reporter genes containing SRE1 in the absence (15-fold) and presence (90-fold) of sterols, abolishing sterol regulation.
SREBP1 is synthesized as a 125-kD precursor that is attached to the nuclear membrane and endoplasmic reticulum (ER). Wang et al. (1994) found that in sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble N-terminal fragment (apparent molecular mass, 68 kD) that translocates to the nucleus. This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG-CoA synthase (142940). Sterols inhibit the cleavage of SREBP1, and the 68-kD nuclear form is rapidly catabolized, thereby reducing transcription. N-acetyl-leucyl-leucyl-norleucinal (ALLN), an inhibitor of neutral cysteine proteases, blocked the breakdown of the 68-kD form and superinduced sterol-regulated genes. Sterol-regulated proteolysis of a membrane-bound transcription factor is a novel mechanism by which transcription can be regulated by membrane lipids.
Cholesterol homeostasis in animal cells is achieved by regulated cleavage of SREBPs, membrane-bound transcription factors. Proteolytic release of the active domains of SREBPs from membranes requires a sterol-sensing protein called SCAP (601510), which forms a complex with SREBPs. In sterol-depleted cells, DeBose-Boyd et al. (1999) found that SCAP escorts SREBPs from the ER to the Golgi, where SREBPs are cleaved by site-1 protease (S1P; 603355). The authors showed that sterols block this transport and abolish cleavage. Relocating active S1P from Golgi to ER by treating cells with brefeldin A or by fusing the ER retention signal KDEL to S1P obviated the SCAP requirement and rendered cleavage insensitive to sterols. DeBose-Boyd et al. (1999) concluded that transport-dependent proteolysis may be a common mechanism to regulate the processing of membrane proteins.
See review by Osborne (2001).
The gene encoding nuclear lamin A/C (LMNA; 150330) is mutated in at least 3 inherited disorders. Two of these, Emery-Dreifuss muscular dystrophy (EDMD; 310300) and a form of dilated cardiomyopathy (CMD1A; 115200), involve muscle defects, and the other, familial partial lipodystrophy (FPLD; 151660), involves loss of subcutaneous adipose tissue. Lloyd et al. (2002) identified proteins interacting with the C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a yeast 2-hybrid interaction screen. Using this approach, SREBP1 was identified as a novel lamin A interactor. A binding site for lamin A was identified in the N-terminal transcription factor domain of SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by FPLD mutations; one EDMD mutation also interfered with the interaction between lamin A and SREBP1. The authors speculated that fat loss seen in laminopathies may be caused in part by reduced binding of the adipocyte differentiation factor SREBP1 to lamin A.
Lin et al. (2005) found that high-fat feeding stimulated expression of both Pgc1-beta (PPARGC1B; 608886) and Srebp1a/1c in mouse liver. Pgc1-beta coactivated the Srebp transcription factor family and stimulated lipogenic gene expression. Furthermore, Pgc1-beta was required for Srebp-mediated lipogenic gene expression. However, unlike Srebp itself, Pgc1-beta reduced fat accumulation in liver while greatly increasing circulating triglycerides and cholesterol in very low density lipoprotein particles. Lin et al. (2005) determined that the stimulation of lipoprotein transport upon Pgc1-beta expression was likely due to the simultaneous coactivation of the liver nuclear hormone receptor, Lxr-alpha (NR1H3; 602423). These data suggested a mechanism through which dietary saturated fats can stimulate hyperlipidemia and atherogenesis.
Synthesis of membrane lipids is critical for cell growth and proliferation. Bengoechea-Alonso et al. (2005) found that G2/M arrest in human cell lines induced expression of a number of SREBP-responsive promoter reporter genes in an SREBP-dependent manner. In addition, the mature forms of SREBP1a and SREBP1c were hyperphosphorylated on C-terminal residues in mitotic cells, whereas mature SREBP2 was not. The transcriptional potency of mature SREBP1 was enhanced in cells arrested in G2/M, and this effect depended on the C-terminal domain of the protein. In agreement with these observations, synthesis of cholesterol was enhanced in G2/M-arrested cells. Bengoechea-Alonso et al. (2005) concluded that the activity of mature SREBP1 is regulated by phosphorylation during the cell cycle, and that SREBP1 provides a link between lipid synthesis, proliferation, and cell growth.
Yang et al. (2006) showed that SREBPs use the evolutionarily conserved ARC105 (607372), also called MED15, subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by nuclear magnetic resonance (NMR) revealed a 3-helix bundle with marked similarity to the CBP/p300 (see 600140) KIX domain. In contrast to SREBPs, the CREB (123810) and c-MYB (189990) activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The C. elegans SREBP homolog Sbp1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes. Yang et al. (2006) found that, like Sbp1, the C. elegans ARC105 homolog Mdt15 is required for fatty acid homeostasis, and showed that both Sbp1 and Mdt15 control transcription of genes governing desaturation of stearic acid to oleic acid. Dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against Sbp1 and Mdt15, including impaired intestinal fat storage, infertility, decreased size, and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of Sbp1 and Mdt15. Yang et al. (2006) concluded that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.
Najafi-Shoushtari et al. (2010) demonstrated that the microRNA miR33B (613486) embedded within an intron of the SREBP1 gene targets the adenosine triphosphate-binding cassette transporter A1 (ABCA1; 600046), an important regulator of high density lipoprotein (HDL) synthesis and reverse cholesterol transport, for posttranscriptional repression. The mature form of miR33B appeared to be coexpressed with SREBP1 in a number of human tissues examined.
Using Lxra and Lxrb (NR1H2; 600380) double-knockout mice and Lxr agonists, Cui et al. (2011) observed Lxr-dependent amelioration of experimental autoimmune encephalomyelitis. Lxr overexpression decreased, whereas Lxr deficiency promoted, cytokine-driven mouse Th17 cell differentiation and polarization in vitro. In mouse, Srebp1 was recruited to the E-box element on the Il17 (603149) promoter upon Lxr activation and interacted with Ahr (600253) to inhibit Il17 transcriptional activity. LXR activation in human cells also suppressed Th17 cell differentiation, promoted SREBP1 expression, and decreased AHR expression. Mutation and coimmunoprecipitation analyses showed that the putative active-site domain of mouse Ahr and the N-terminal acidic region of mouse Srebp1 were essential for Ahr-Srebp1 interaction. Cui et al. (2011) concluded that a downstream target of LXR, SREBP1, antagonizes AHR to suppress Th17 cell generation and autoimmunity.
Han et al. (2015) showed in mice that Creb-regulated transcription coactivator-2 (CRTC2; 608972) functions as a mediator of mTOR (601231) signaling to modulate coat protein complex II (COPII)-dependent Srebp1 processing. Crtc2 competes with Sec23A (610511), a subunit of the COPII complex, to interact with Sec31A (610257), another COPII subunit, thus disrupting Srebp1 transport. During feeding, mTOR phosphorylates Crtc2 and attenuates its inhibitory effect on COPII-dependent Srebp1 maturation. As hepatic overexpression of an mTOR-defective Crtc2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrated how the transcriptional coactivator Crtc2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.
IFAP Syndrome 2
In a Chinese mother and daughter and 8 unrelated individuals with follicular ichthyosis, atrichia, and photophobia (IFAP2; 619016), Wang et al. (2020) identified heterozygosity for a missense mutation in the SREBF1 gene (R527C; 184756.0001) that segregated with disease and was not found in public variant databases. Another Chinese mother and daughter with IFAP were heterozygous for a 1-bp deletion in SREBF1 (184756.0002), and an affected Austrian girl was heterozygous for a different missense mutation in SREBF1 (L530P; 184756.0003). Functional analysis of the SREBF1 variants demonstrated impaired S1P cleavage that prohibited nuclear translocation of the transcriptionally active form of SREBF1, resulting in significantly lower transcriptional activity with the mutants compared to wildtype SREBF1.
Hereditary Mucoepithelial Dysplasia
In 7 patients from 4 families with hereditary mucoepithelial dysplasia (HMD; 158310), Morice-Picard et al. (2020) identified heterozygosity for 2 different missense mutations in the SREBF1 gene, both occurring at the same R557 residue: an R557C substitution (184756.0004) in 2 unrelated patients, and an R557H substitution (184756.0005) in 4 affected members of a family and an unrelated patient.
In a Mexican father and daughter with HMD, Chacon-Camacho et al. (2020) performed WES and identified heterozygosity for the same R557C mutation in the SREBF1 gene that had been reported previously by Morice-Picard et al. (2020).
The synthesis of cholesterol and its uptake from plasma LDL are regulated by 2 membrane-bound transcription factors, SREBP1 and SREBP2. Shimano et al. (1997) used homologous recombination to generate mice with disruptions in the gene coding the 2 isoforms of SREBP1, which they termed SREBP1a and SREBP1c. Heterozygous gene-disrupted mice were phenotypically normal, but 50 to 85% of the homozygous -/- mice died in utero at embryonic day 11. The surviving -/- mice appeared normal at birth and throughout life. Their livers expressed no functional SREBP1, but there was a 1.5-fold upregulation of SREBP2 at the level of mRNA and a 2- to 3-fold increase in the amount of mature SREBP2 in liver nuclei. Previous studies had shown that SREBP2 is much more potent than SREBP1c, the predominant hepatic isoform of SREBP1, in activating transcription of genes encoding enzymes of cholesterol synthesis. Elevated levels of mRNAs for 4 enzymes of cholesterol synthesis were observed. Cholesterol synthesis, as measured by the incorporation of tritium-labeled water, was elevated 3-fold in the livers of the -/- mice, and hepatic cholesterol content was increased by 50%. Thus, Shimano et al. (1997) concluded that SREBP2 can replace SREBP1 in regulating cholesterol synthesis in livers of mice and that the higher potency of SREBP2 leads to excessive hepatic cholesterol synthesis in these animals.
Shimomura et al. (1998) produced transgenic mice that overexpressed nuclear SREBP1C in adipose tissue under the control of the adipocyte-specific aP2 (600434) enhancer/promoter. These mice exhibited many of the features of congenital generalized lipodystrophy (BSCL; 269700). White fat failed to differentiate fully, and the size of the white fat deposits was markedly decreased. Brown fat was hypertrophic and contained fat-laden cells resembling immature white fat. Levels of mRNA encoding adipocyte differentiation markers, including leptin (164160), were reduced, but levels of PREF1 (176290) and TNF-alpha (191160) were increased. Marked insulin resistance with 60-fold elevation in plasma insulin was observed. Diabetes mellitus with elevated blood glucose of greater than 300 mg/dl that failed to decline when insulin was injected was also seen. The transgenic mice had fatty liver from birth and developed elevated plasma triglyceride levels later in life.
By studying lipodystrophic and obese (ob/ob) mice, Shimomura et al. (2000) showed that chronic hyperinsulinemia downregulates the mRNA for IRS2 (600797), an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS2 deficiency, insulin continues to stimulate production of SREBP1c. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice.
Using oligonucleotide microarray and Northern blot analyses to analyze gene expression, Tobe et al. (2001) detected increased expression of SREBP1 in insulin-resistant Irs2-deficient mouse liver. Tobe et al. (2001) also detected an increase in the expression of several SREBP1 downstream genes involved in fatty acid synthesis. Tobe et al. (2001) showed that leptin resistance contributes to the upregulation of the SREBP1 gene by demonstrating that high dose leptin administration reduced food intake and body weight, and ameliorated SREBP1 overexpression in Irs2-deficient mice.
Nagata et al. (2004) noted that a high-fructose diet in rats induces metabolic derangements similar to those found in the metabolic syndrome, which is a constellation of features including hyperlipidemia, visceral obesity, impaired glucose tolerance, and hyperinsulinemia. In a group of 10 strains of inbred mice, which could be separated into those that developed the metabolic syndrome in response to a high-fructose diet (CBA) and those that did not develop the syndrome (DBA), the authors found that hepatic mRNA expression of the SREBP1 protein was enhanced in CBA mice, but not in DBA mice. Sequence analysis showed that the nucleotide sequence at -468 bp in the SREBP1 promoter was guanine in the CBA group and adenine in the DBA group. In cultured hepatocytes from CBA mice, the activity of the SREBP1 promoter was significantly increased by 2.4- and 2.2-fold in response to fructose or insulin, respectively, whereas the activity of the DBA SREBP1 promoter responded to insulin but not to fructose. The authors concluded that genetic alterations of transcriptional regulation at the SREBP1 promoter explain the different responses to a high-fructose diet in these 2 strains.
In cortical neuron culture, Taghibiglou et al. (2009) found that activation of NMDA receptors resulted in increased activation and nuclear accumulation of SREBP1. The activation was primarily mediated by the NR2B (138252) subunit-containing receptor. Inhibition of NMDAR-dependent SREBP1 activation by cholesterol decreased NMDA-induced excitotoxic cell death. Similarly, shRNA against SREBP1 also resulted in decreased cell death in culture. These findings implicated SREBP1 as a mediator of NMDA-induced excitotoxicity. NMDAR-mediated activation of SREBP1 was shown to result from increased INSIG1 (602055) degradation, which could be inhibited with an interference peptide. In a rat model of focal ischemic stroke, systemic administration of the INSIG1 interference peptide prevented SREBP1 activation, substantially reduced neuronal damage, and improved behavioral outcome.
In a Chinese mother and daughter (family 2) with follicular ichthyosis, atrichia, and photophobia (IFAP2; 619016), Wang et al. (2020) identified heterozygosity for a c.1579C-T transition (c.1579C-T, NM_004176.3) in the SREBF1 gene, resulting in an arg527-to-cys (R527C) substitution at a highly conserved residue within a motif crucial for S1P recognition and cleavage. The R527C mutation was also detected in 8 unrelated IFAP patients of varying ethnicities, including Chinese, German, Congolese, Italian, African American, and Indian. The variant, which was not found in the ExAC or gnomAD databases, was confirmed to have arisen de novo in 4 of the sporadic cases. Nuclear extracts from transiently transfected HEK293 cells expressing the R527C mutant under sterol-free conditions did not show the 71-kD band corresponding to the transcriptionally active cleaved form of SREBF1 that was seen in cells expressing wildtype SREBF1. Immunostained transfected cells showed the most pronounced signal in the nuclei of wildtype cells, whereas nuclear staining was barely discernable in cells expressing the R527C mutant; in the latter cells, signal was largely restricted to the cytoplasm, suggesting that the mutant failed to translocate to the nucleus. In addition, the R527C mutant showed significantly reduced transcriptional activity, to only 33% of wildtype activity. RNA sequencing of scalp skin from the affected mother and daughter in family 2 revealed a dramatic reduction in transcript levels of LDLR (606945) and of keratin genes known to be expressed in the outer root sheath of hair follicles. Scalp keratinocytes also showed an increased rate of apoptosis, which the authors suggested might contribute to skin hyperkeratosis and hypotrichosis.
In a Chinese mother and daughter (family 1) with follicular ichthyosis, moderate to severe hypotrichosis, and photophobia (IFAP2; 619016), Wang et al. (2020) identified heterozygosity for an in-frame 3-bp deletion (c.1582_1584del, NM_004176.3) in the SREBF1 gene, resulting in deletion of the asn residue at position 528 (N528del), located within a motif crucial for S1P recognition and cleavage. The mutation was not found in the ExAC or gnomAD databases. Nuclear extracts from transiently transfected HEK293 cells expressing the N528del mutant under sterol-free conditions did not show the 71-kD band corresponding to the transcriptionally active cleaved form of SREBF1 that was seen in cells expressing wildtype SREBF1. Immunostained transfected cells showed the most pronounced signal in the nuclei of wildtype cells, whereas nuclear staining was barely discernable in cells expressing the N528del mutant; in the latter cells, signal was largely restricted to the cytoplasm, suggesting that the mutant failed to translocate to the nucleus. In addition, the N528del mutant showed significantly reduced transcriptional activity, to only 41% of wildtype activity. RNA sequencing of scalp skin from the affected mother and daughter revealed a dramatic reduction in transcript levels of LDLR (606945) and of keratin genes known to be expressed in the outer root sheath of hair follicles. Scalp keratinocytes also showed an increased rate of apoptosis, which the authors suggested might contribute to skin hyperkeratosis and hypotrichosis.
In a 7-year-old Austrian girl (individual 10) with marked hypotrichosis and photophobia (IFAP2; 619016), Wang et al. (2020) identified heterozygosity for a de novo c.1589T-C transition (c.1589T-C, NM_004176.3) in the SREBF1 gene, resulting in a leu530-to-pro (L530P) substitution at a highly conserved residue within a motif crucial for S1P recognition and cleavage. The mutation was not found in the proband's healthy parents, or in the ExAC or gnomAD databases. Nuclear extracts from transiently transfected HEK293 cells expressing the L530P mutant under sterol-free conditions did not show the 71-kD band corresponding to the transcriptionally active cleaved form of SREBF1 that was seen in cells expressing wildtype SREBF1. Immunostained transfected cells showed the most pronounced signal in the nuclei of wildtype cells, whereas nuclear staining was barely discernable in cells expressing the L530P mutant; in the latter cells, signal was largely restricted to the cytoplasm, suggesting that the mutant failed to translocate to the nucleus. In addition, the L530P mutant showed significantly reduced transcriptional activity, to only 28% of wildtype activity.
In a 19-year-old woman (P1) and an unrelated 20-year-old woman (P2) with hereditary mucoepithelial dysplasia (HMD; 158310), Morice-Picard et al. (2020) identified heterozygosity for a c.1669C-T transition (c.1669C-T, NM_001005291.2) in exon 9 of the SREBF1 gene, resulting in an arg557-to-cys (R557C) substitution at a highly conserved residue, essential for cleavage, within the luminal loop. The mutation was discrepantly noted as occurring in exon 18 in Figure 2 of the report. The unaffected parents of P1 did not carry the mutation, indicating that it arose de novo in the proband, and the R557C variant was also not found in the dbSNP, 1000 Genomes Project, or gnomAD databases.
In a Mexican father and daughter with HMD, Chacon-Camacho et al. (2020) identified heterozygosity for the R557C mutation in the SREBF1 gene.
In a 17-year-old girl (P3) with hereditary mucoepithelial dysplasia (HMD; 158310), and 4 affected individuals (patients F1 to F4) over 3 generations of a family segregating autosomal dominant HMD (family A), Morice-Picard et al. (2020) identified heterozygosity for a c.1670G-A transition (c.1670G-A, NM_001005291.2) in exon 9 of the SREBF1 gene, resulting in an arg557-to-his (R557H) substitution at a highly conserved residue, essential for cleavage, within the luminal loop. The mutation was discrepantly noted as occurring in exon 18 in Figure 2 of the report. The unaffected son of proband F1 from family A did not carry the mutation, which was also not found in the dbSNP, 1000 Genomes Project, or gnomAD databases.
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