HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase [Homo sapiens (human)] - Gene

Summary

Official Symbol: HMGCRprovided by HGNC
Official Full Name: 3-hydroxy-3-methylglutaryl-CoA reductaseprovided by HGNC
Primary source: HGNC:HGNC:5006
See related: Ensembl:ENSG00000113161 MIM:142910
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: LDLCQ3
Summary: HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
Expression: Ubiquitous expression in brain (RPKM 31.2), colon (RPKM 23.2) and 25 other tissues See more
Orthologs: mouse all

Genomic context

Location:: 5q13.3

Exon count:: 23

Annotation release	Status	Assembly	Chr	Location
109.20200522	current	GRCh38.p13 (GCF_000001405.39)	5	NC_000005.10 (75336334..75362116)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	5	NC_000005.9 (74632159..74657926)

Chromosome 5 - NC_000005.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

Go to the top of the page Help

Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

Go to the top of the page Help

See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

Go to the top of the page Help

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

In this study, it's demonstrated that doxorubicin exerts its anti-cancer effect via modulation of cholesterol synthesis through downregulation of HMG-CoA reductase (HMG-CR) expression, which is mediated by the epidermal growth factor receptor(EGFR)-Src pathway.
Title: Anti-cancer effect of doxorubicin is mediated by downregulation of HMG-Co A reductase via inhibition of EGFR/Src pathway.
lanosterol is a bona fide endogenous regulator that specifically promotes HMGCR degradation, and that other C4-dimethylated sterol intermediates may regulate both HMGCR degradation and SREBP-2 cleavage
Title: Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.
rs3846662:C>A HMGCR affect the blood apoB levels which might be predictive of cardiovascular disease risk. [Meta- analysis]
Title: A meta-analysis of Italian and Estonian individuals shows an effect of common variants in <i>HMGCR</i> on blood apoB levels.
Statin treatment led to an upregulation of HMGCR mRNA and protein expression by up to sixfolds in the statin-resistant cells lines (p < 0.001), but no alterations of HMGCR were observed in the statin-sensitive MDA-MB-231 and MDA-MB-468 cells. The knockdown of HMGCR prior to statin treatment sensitized the resistant cell lines.
Title: Induction of 3-hydroxy-3-methylglutaryl-CoA reductase mediates statin resistance in breast cancer cells.
Genetically proxied inhibition of HMG-CoA reductase was significantly associated with lower odds of epithelial ovarian cancer.
Title: Association Between Genetically Proxied Inhibition of HMG-CoA Reductase and Epithelial Ovarian Cancer.
Anti-HMGCR myopathy can resemble limb-girdle muscular dystrophy (LGMD). Diagnosis of patients with a LGMD-like presentation of anti-HMGCR myopathy is critical because these patients may respond favorably to immunotherapy, especially those with shorter disease duration.
Title: Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy.
Assessment of the molecular mechanism demonstrated that SREBP2 interacted with cMyc and cooperated with cMyc to activate HMGCR expression.
Title: SREBP2 is upregulated in esophageal squamous cell carcinoma and co‑operates with c‑Myc to regulate HMGCR expression.
Results find that schnyder corneal dystrophy (SCD)-associated UBIAD1 mutations decrease HMGCR degradation and subsequently increase cholesterol biosynthesis in the cornea.
Title: Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase.
Study found a significant association of HMGCR rs3846662 with mild cognitive impairment (MCI) in females independent of APOE [epsilon]4. In contrast, it revealed that the association of SIRT1 rs7895833 with MCI was dependent on with APOE [epsilon]4. Data also showed that hypermethylation of APOE in MCI was independent of APOE [epsilon]4.
Title: Significant association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) rs3846662 and sirtuin 1 (SIRT1) rs7895833 and apolipoprotein E (APOE) hypermethylation with mild cognitive impairment (MCI).
Study showed that 5'isomiRNA of miR-140-3p (miR-140-3p-1) was preferentially expressed during the entire spectrum of preneoplastic progression in the MCF10A-derived triple negative breast cancer model. miR-140-3p-1 and its novel direct gene targets, HMGCR and HMGCS1, key enzymes in the cholesterol biosynthesis pathway, were deregulated in the normal-to-preneoplastic transition.
Title: The isomiR-140-3p-regulated mevalonic acid pathway as a potential target for prevention of triple negative breast cancer.

Submit: New GeneRIF Correction See all GeneRIFs (112)

Phenotypes

Go to the top of the page Help

Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

NHGRI GWAS Catalog

Description
A genome wide association study identifies common variants associated with lipid levels in the Chinese population. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Biological, clinical and population relevance of 95 loci for blood lipids. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Common variants at 30 loci contribute to polygenic dyslipidemia. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Discovery and refinement of loci associated with lipid levels. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Genetic variants influencing circulating lipid levels and risk of coronary artery disease. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. NHGRI GWA Catalog NHGRI GWA CatalogPubMed

Variation

Go to the top of the page Help

See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

Go to the top of the page Help

Protein interactions

Protein	Gene	Interaction	Pubs
Nef	nef	HIV-1 Nef modulates expression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in Jurkat cells	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

Go to the top of the page Help

Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

Go to the top of the page Help

Markers

RH47294 (e-PCR)
- UniSTS:36389

GDB:177804 (e-PCR)
- UniSTS:154965

GDB:181537 (e-PCR)
- UniSTS:155263

D5S2670 (e-PCR)
- UniSTS:67513

D5S2478 (e-PCR)
- UniSTS:8158

EST7D6 (e-PCR)
- UniSTS:263414

Homology

Homologs of the HMGCR gene: The HMGCR gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C.elegans, S.cerevisiae, K.lactis, E.gossypii, S.pombe, M.oryzae, N.crassa, A.thaliana, rice, and frog.
Orthologs from Annotation Pipeline: 292 organisms have orthologs with human gene HMGCR
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
NADPH binding	IDA Inferred from Direct Assay more info	PubMed
hydroxymethylglutaryl-CoA reductase (NADPH) activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
hydroxymethylglutaryl-CoA reductase (NADPH) activity	IDA Inferred from Direct Assay more info	PubMed
hydroxymethylglutaryl-CoA reductase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
hydroxymethylglutaryl-CoA reductase activity	IDA Inferred from Direct Assay more info	PubMed
identical protein binding	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein phosphatase 2A binding	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
aging	IEA Inferred from Electronic Annotation more info
cholesterol biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
cholesterol biosynthetic process	TAS Traceable Author Statement more info
coenzyme A metabolic process	IEA Inferred from Electronic Annotation more info
isoprenoid biosynthetic process	IBA Inferred from Biological aspect of Ancestor more info	PubMed
myoblast differentiation	IEA Inferred from Electronic Annotation more info
negative regulation of MAP kinase activity	IEA Inferred from Electronic Annotation more info
negative regulation of amyloid-beta clearance	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of blood vessel diameter	IEA Inferred from Electronic Annotation more info
negative regulation of insulin secretion involved in cellular response to glucose stimulus	IEA Inferred from Electronic Annotation more info
negative regulation of protein catabolic process	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of protein secretion	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of striated muscle cell apoptotic process	IEA Inferred from Electronic Annotation more info
negative regulation of wound healing	IEA Inferred from Electronic Annotation more info
oxidation-reduction process	IEA Inferred from Electronic Annotation more info
positive regulation of ERK1 and ERK2 cascade	IEA Inferred from Electronic Annotation more info
positive regulation of cardiac muscle cell apoptotic process	IEA Inferred from Electronic Annotation more info
positive regulation of skeletal muscle tissue development	IEA Inferred from Electronic Annotation more info
positive regulation of smooth muscle cell proliferation	IEA Inferred from Electronic Annotation more info
positive regulation of stress-activated MAPK cascade	IEA Inferred from Electronic Annotation more info
regulation of cholesterol biosynthetic process	TAS Traceable Author Statement more info
regulation of lipid metabolic process	TAS Traceable Author Statement more info
response to ethanol	IEA Inferred from Electronic Annotation more info
response to nutrient	IEA Inferred from Electronic Annotation more info
sterol biosynthetic process	IBA Inferred from Biological aspect of Ancestor more info	PubMed
ubiquinone metabolic process	IEA Inferred from Electronic Annotation more info
visual learning	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
endoplasmic reticulum	IDA Inferred from Direct Assay more info	PubMed
endoplasmic reticulum membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
endoplasmic reticulum membrane	TAS Traceable Author Statement more info	PubMed
integral component of membrane	IEA Inferred from Electronic Annotation more info
peroxisomal membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
peroxisomal membrane	IDA Inferred from Direct Assay more info	PubMed

General protein information

Go to the top of the page Help

Preferred Names: 3-hydroxy-3-methylglutaryl-Coenzyme A reductase

Names: 3-hydroxy-3-methylglutaryl CoA reductase (NADPH); HMG-CoA reductase; hydroxymethylglutaryl-CoA reductase

NP_000850.1

EC 1.1.1.34

NP_001124468.1

EC 1.1.1.34

NP_001351116.1

EC 1.1.1.34

XP_011541659.1

EC 1.1.1.34

XP_011541660.1

EC 1.1.1.34

XP_011541661.1

EC 1.1.1.34

NCBI Reference Sequences (RefSeq)

Go to the top of the page Help

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_011449.1 RefSeqGene

Range

5053..29934

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_000859.3 → NP_000850.1 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 1

See identical proteins and their annotated locations for NP_000850.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the longer isoform (1). Variants 1 and 3 both encode the same isoform (1).

Source sequence(s)

AA648735, BC033692, CN278665, M11058, M62627

Consensus CDS

CCDS4027.1

UniProtKB/Swiss-Prot

P04035

UniProtKB/TrEMBL

A0A024RAP2

Related

ENSP00000287936.4, ENST00000287936.9

Conserved Domains (1) summary

TIGR00920
Location:1 → 888

2A060605; 3-hydroxy-3-methylglutaryl-coenzyme A reductase
NM_001130996.1 → NP_001124468.1 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 2

See identical proteins and their annotated locations for NP_001124468.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an in-frame coding exon in the middle region, as compared to variant 1. The resulting isoform (2) is shorter than isoform 1.

Source sequence(s)

AA648735, BC033692, CN278665, M62627

Consensus CDS

CCDS47234.1

UniProtKB/Swiss-Prot

P04035

Related

ENSP00000340816.5, ENST00000343975.9

Conserved Domains (1) summary

TIGR00920
Location:1 → 835

2A060605; 3-hydroxy-3-methylglutaryl-coenzyme A reductase
NM_001364187.1 → NP_001351116.1 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 1

Status: REVIEWED

Description

Transcript Variant: This variant (3) differs in the 5' UTR compared to variant 1. Variants 1 and 3 both encode the same isoform (1).

Source sequence(s)

AC008897

Related

ENSP00000426745.1, ENST00000511206.5

Conserved Domains (1) summary

TIGR00920
Location:1 → 888

2A060605; 3-hydroxy-3-methylglutaryl-coenzyme A reductase

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 109.20200522

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p13 Primary Assembly

Genomic

NC_000005.10 Reference GRCh38.p13 Primary Assembly

Range

75336334..75362116

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_011543357.1 → XP_011541659.1 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform X1

UniProtKB/Swiss-Prot

P04035

Conserved Domains (3) summary

cd00643
Location:485 → 891

HMG-CoA_reductase_classI; Class I hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)

TIGR00920
Location:21 → 908

2A060605; 3-hydroxy-3-methylglutaryl-coenzyme A reductase

cl21543
Location:108 → 238

MMPL; MMPL family
XM_011543359.1 → XP_011541661.1 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform X3

Conserved Domains (3) summary

cd00643
Location:485 → 838

HMG-CoA_reductase_classI; Class I hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)

TIGR00920
Location:21 → 855

2A060605; 3-hydroxy-3-methylglutaryl-coenzyme A reductase

cl21543
Location:108 → 238

MMPL; MMPL family
XM_011543358.1 → XP_011541660.1 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform X2

See identical proteins and their annotated locations for XP_011541660.1

UniProtKB/Swiss-Prot

P04035

UniProtKB/TrEMBL

A0A024RAP2

Conserved Domains (1) summary

TIGR00920
Location:1 → 888

2A060605; 3-hydroxy-3-methylglutaryl-coenzyme A reductase