A functional mutation in the LDLR promoter (−139C&gt;G) in a patient with familial hypercholesterolemia

Smith, Andrew J.; Ahmed, Fayha; Nair, Devi; Whittall, R.; Wang, Darrell; Taylor, Alison; Norbury, Gail; Humphries, Steve E.

doi:10.1038/sj.ejhg.5201897

Cited by 24 publications

(15 citation statements)

References 10 publications

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“…Promoter mutation-induced diseases have been reported previously (Plenge et al, 1997;Almeida et al, 2006;Guyant-Marechal et al, 2007;Smith et al, 2007). There is still no report regarding the relationship between promoter mutation and epilepsy, although it has been proved that SME is caused by reduced levels of sodium channels and loss of function resulting from SCN1A abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Long

Zhao

et al. 2008

J of Neuroscience Research

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Voltage-gated sodium channels play critical roles in the excitability of the brain. A decreased level of Na(v)1.1 has been identified as the cause of severe myoclonic epilepsy in infancy. In the present study, we identified the transcription start site and three 5'-untranslated exons of SCN1A by using 5'-full RACE. The 2.5-kb region upstream of the transcription start site was targeted as a potential location of the promoter. The 2.5-kb genomic fragment (P(2.5), from +26 to -2,500) and the 2.7-kb fragment (P(2.7), P(2.5) combined with the 227-bp 5'-untranslated exons) were cloned to produce luciferase constructs. The P(2.5) and the P(2.7) drove luciferase gene expression in the human neuroblastoma cell line SH-SY5Y but not in the human embryonic kidney cell line HEK-293. The 5'-untranslated exons could greatly enhance gene expression in SH-SY5Y cells. The P(2.7) could be used as a functional unit to study the role of SCN1A noncoding sequences in gene expression. These findings will also help in exploring the possibility of promoter mutant-induced diseases and revealing the mechanism underlying the regulation of SCN1A expression in the normal brain.

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Section: Discussionmentioning

confidence: 99%

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Long

Zhao

et al. 2008

J of Neuroscience Research

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“…The substituted nucleotide is not a strongly conserved base of the SP1 binding site, and this mutation reduced SP1 binding affinity and led to FH (26). In addition, two more mutations in the LDLR gene, -49C>T and -139C>G, have been identified, with one of these shown to induce the loss of SP1 binding in a patient with FH (27,28). The SPI1 gene encodes an ETS-domain transcription factor that activates gene expression during myeloid and B-lymphoid cell development.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome and miRNA network analysis of familial hypercholesterolemia

Chen

Wang

Jiang

2013

International Journal of Molecular Medicine

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Familial hypercholesterolemia (FH) is a genetic disorder characterized by a high serum concentration of low-density lipoprotein (LDL) cholesterol. The high LDL cholesterol level leads to an excess deposition of cholesterol in the arterial walls and accelerated atherosclerosis, thereby increasing the risk of premature coronary heart disease. In the present study, we used a DNA microarray approach to identify gene expression profiles that distinguish patients with FH from healthy control subjects. Furthermore, transcription factors (TFs), microRNAs (miRNAs), target genes and pathways were analyzed to explore the potential transcriptional interactions occurring in FH. Publicly available microarray and regulation data were used to construct a regulatory network to identify additional genes related to FH and their interactions. The results revealed that specificity protein 1 (SP1), signal transducer and activator of transcription 1 (STAT1) and spleen focus forming virus (SFFV) proviral integration oncogene spi1 (SPI1) play a central role in the FH regulatory network. In addition, the TF, upstream transcription factor 2, c-fos interacting (USF2) and the gene, Wiskott-Aldrich syndrome (WAS), were identified to be associated with FH, although no reports for these proteins exist in the literature. Overall, transcriptional network analysis proved to be effective approach to identify novel targets for FH therapy.

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“…For instance, long noncoding RNA (lncRNA) facilitates chromatin remodeling, small nuclear RNA (snRNA) mediates splicing, and cytoplasmic microRNA (miRNA) destabilizes RNA and/or microRNA genetics of lipid-related disorders affi nity for one or more TFs, and the resulting effect on transcription could directly infl uence lipid metabolic pathways. For example, several single nucleotide polymorphisms (SNP) in the core promoter region of the low-density lipoprotein receptor ( LDLR ) gene have been shown to abolish binding of the transcription factor Sp1 (49)(50)(51)(52)(53), which leads to familial hypercholesterolemia (FH). As another example, a very recent study demonstrated that the minor allele of the SNP rs12740374, located within an LRE at the 1p13 locus, dramatically increases the binding affi nity for the transcription factor CEBPA, which in turn alters the hepatic expression of the gene sortilin 1 ( SORT1 ), leading to impaired lipoprotein metabolism ( 54,55 ).…”

Section: Hepatic Mirnas and Lipid Homeostasismentioning

confidence: 99%

Needles in the genetic haystack of lipid disorders: single nucleotide polymorphisms in the microRNA regulome

Sethupathy

2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org inhibits protein translation. Although mammalian miRNAs were not discovered until a decade ago ( 2 ), they have rapidly emerged as important posttranscriptional regulators of gene expression in a wide variety of biological pathways ( 3 ). Moreover, miRNAs have been demonstrated to be i ) stable plasma biomarkers of physiological status ( 4,5 ), ii ) novel intercellular signaling molecules ( 6 ), iii ) etiological factors in complex diseases ( 7 ), and iv ) promising therapeutic targets ( 8,9 ).In 2002, miR-122 was found to be the most abundant miRNA in the liver, accounting for greater than 70% of all hepatic miRNA expression ( 2 ). More recent, high-throughput small RNA sequencing (smRNA-seq) studies have confi rmed this fi nding and, notably, have not detected miR-122 in any other cell type ( 10 ). Circulating levels of miR-122 have been identifi ed as a clinically relevant biomarker of liver injury ( 11, 12 ), cirrhosis ( 13 ), necroinfl ammation ( 14 ), and hyperlipidemia ( 15 ). In 2005, miR-122 was also shown to directly promote the replication of the hepatitis C virus (HCV) ( 16 ). Subsequently, it was demonstrated that inhibition of miR-122 by a locked nucleic acid (LNA) antisense oligonucleotide diminishes HCV viremia in chimpanzees ( 17 ). The anti-miR-122 LNA molecule (known as Miravirsen) has since advanced to phase II human clinical trials for hepatitis C treatment, and it appears to induce a potent antiviral effect in the absence of evident liver or cardiac toxicities ( 18 ).miR-122 was also the fi rst miRNA identifi ed as a regulator of lipid metabolism ( 19 ). In 2006, antisense oligonucleotide-mediated inhibition of miR-122 (ASO-miR-122) in mice reduced plasma cholesterol levels, decreased hepatic lipid synthesis, and enhanced hepatic fatty acid oxidation ( 19 ). Moreover, the ASO-miR-122 was also able to reverse the effects of diet-induced obesity by reducing hepatic steatosis. Abbreviations: LRE, long-range regulatory element; miRNA (miR), microRNA; miR-122, miRNA-122; pre-miRNA, miRNA precursor; primiRNA, primary miRNA; ORF, open reading frame; RISC, RNA-induced silencing complex; SNP, single nucleotide polymorphism; TF, transcriptional factor; UTR, untranslated region.

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A functional mutation in the LDLR promoter (−139C>G) in a patient with familial hypercholesterolemia

Cited by 24 publications

References 10 publications

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Transcriptome and miRNA network analysis of familial hypercholesterolemia

Needles in the genetic haystack of lipid disorders: single nucleotide polymorphisms in the microRNA regulome

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A functional mutation in the LDLR promoter (−139C>G) in a patient with familial hypercholesterolemia

Cited by 24 publications

References 10 publications

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Nav1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Nav1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Transcriptome and miRNA network analysis of familial hypercholesterolemia

Needles in the genetic haystack of lipid disorders: single nucleotide polymorphisms in the microRNA regulome

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Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons