Alternative titles; symbols
HGNC Approved Gene Symbol: HMGCR
Cytogenetic location: 5q13.3 Genomic coordinates (GRCh38): 5:75,336,529-75,362,116 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q13.3 | [Low density lipoprotein cholesterol level QTL 3] | 620410 | 3 | |
| [Statins, response to] | 620410 | 3 | ||
| Muscular dystrophy, limb-girdle, autosomal recessive 28 | 620375 | Autosomal recessive | 3 |
HMG-CoA reductase (EC 1.1.1.88), a transmembrane glycoprotein of the endoplasmic reticulum, is the rate-limiting enzyme in cholesterol biosynthesis and converts HMG-CoA to mevalonate. Mevalonate can be converted to cholesterol through a series of enzymatic reactions; it can also serve as the precursor for several nonsterol isoprenoid compounds such as ubiquinone, dolichol, and the isopentenyl group of tRNA. The activity of HMGCR is finely regulated by a negative feedback mechanism in which cholesterol and the other end products of the metabolic pathway suppress the enzyme in a multivalent fashion. Cholesterol suppresses reductase activity primarily by inhibiting the rate of transcription of the reductase gene (summary by Reynolds et al., 1984). See review by Goldstein and Brown (1990).
Osborne et al. (1985) determined that the promoter region of the hamster Hmgcr gene contains 5 copies of the hexanucleotide sequence CCGCCC, or its inverse complement GGGCGG, in addition to sequences necessary for cholesterol-dependent transcriptional repression.
Luskey (1987) determined that the human HMGCR gene has several transcriptional start sites that generate relatively short 5-prime UTRs of 73 to 105 nucleotides. As in the hamster Hmgcr gene, this upstream region provides sites for statin-dependent induction and sterol-dependent suppression. However, in contrast with hamster Hmgcr, human HMGCR has only a single GGGCGG sequence.
Using DNA probes in somatic cell hybrids, Henry et al. (1985), Lindgren et al. (1985), and Mohandas et al. (1986) assigned HMGCR to chromosome 5. In situ hybridization in the hands of Lindgren et al. (1985) permitted regionalization to 5q13.3-q14. By the same method, Humphries et al. (1985) placed the HMGCR gene in band 5q12.
Although catalyzing a rate-limiting step in cholesterol biosynthesis (see 143890) is the best known role of HMG-CoA reductase, the enzyme also participates in the production of a wide variety of other compounds. Some clinical benefits attributed to inhibitors of HMG-CoA reductase appear to be independent of any serum cholesterol-lowering effect. Van Doren et al. (1998) described a new cholesterol-independent role for the enzyme, in regulating a developmental process, primordial germ cell migration. They showed that in Drosophila this enzyme is highly expressed in the somatic gonad and that it is necessary for primordial germ cells to migrate to this tissue. Misexpression of HMG-CoA reductase was sufficient to attract primordial germ cells to tissues other than the gonadal mesoderm. Van Doren et al. (1998) concluded that the regulated expression of HMG-CoA reductase has a critical developmental function in providing spatial information to guide migrating primordial germ cells.
Sever et al. (2003) showed that degradation of HMG-CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the endoplasmic reticulum (ER) protein INSIG1 (602055). Accelerated degradation was inhibited by overexpression of the sterol-sensing domain of SCAP (601510), suggesting that both proteins bind to the same site on INSIG1. Whereas INSIG1 binding to SCAP led to ER retention, INSIG1 binding to HMG-CoA reductase led to accelerated degradation that could be blocked by proteasome inhibitors. The authors concluded that INSIG1 plays an essential role in the sterol-mediated trafficking of HMG-CoA reductase and SCAP.
Istvan and Deisenhofer (2001) determined structures of the catalytic portion of human HMG-CoA reductase complexed with 6 different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMG-CoA reductase, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.
HMG-CoA reductase inhibitors promote cellular apoptosis and differentiation in many cancer cells; these effects are unrelated to lipid reduction. Wang et al. (2003) showed that lovastatin, an HMG-CoA reductase inhibitor, could induce apoptosis and differentiation in anaplastic thyroid cancer cells. Their results showed that at a higher dose (50 mM), lovastatin induced apoptosis of anaplastic thyroid cancer cells, whereas at a lower dose (25 mM), it promoted 3-dimensional cytomorphologic differentiation. It also induced increased secretion of thyroglobulin (188450) by anaplastic thyroid cancer cells. They concluded that lovastatin not only induces apoptosis, but also promotes redifferentiation in anaplastic thyroid cancer cells, and suggested that it and other HMG-CoA reductase inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer.
Low Density Lipoprotein Cholesterol Level Quantitative Trait Locus 3
In a study of 10 candidate genes in relation to response to statin therapy, Chasman et al. (2004) found that 2 common and tightly linked SNPs in the gene encoding HMG-CoA reductase (142910.0001), the target enzyme that is inhibited by pravastatin, were significantly associated with reduced efficacy of pravastatin therapy in reducing cholesterol level (see LDLCQ3, 620410). Compared with individuals homozygous for the major allele of 1 of the SNPs, individuals with a single copy of the minor allele had a 22% smaller reduction in total cholesterol.
Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs12654264 of HMGCR (142910.0002), had previously been associated with elevated low density lipoprotein (LDL) cholesterol (LDLCQ3; 620410) or lower high density lipoprotein (HDL) cholesterol. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles.
In a genomewide association study (GWAS) of cholesterol- and triglyceride-related loci involving over 17,000 individuals aged 18 to 104 years from geographic regions spanning from the Nordic countries to Southern Europe, Aulchenko et al. (2009) established 22 loci associated with serum lipid levels at a genomewide significance level (p less than 5 x 10(-8)), including 16 loci that had been identified by previous GWAS. This included a region near the HMGCR gene characterized by rs3846662 (p = 2.5 x 10(-19) for total cholesterol, p = 1.5 x 10(-11) for LDL cholesterol).
In a GWAS for plasma lipids in more than 100,000 individuals of European ancestry, Teslovich et al. (2010) identified 95 significantly associated loci (p less than 5 x 10(-8)). Teslovich et al. (2010) identified rs12916 in the HMGCR gene as having an effect on total cholesterol and LDL cholesterol with an effect size of +2.84 mg per deciliter and a p value of 9 x 10(-47).
Expression of an alternatively spliced HMGCR transcript lacking exon 13 has been implicated in the variation of LDL cholesterol. Yu et al. (2014) sought to identify molecules that regulate HMGCR alternative splicing. They chose to follow HNRNPA1 (164017), since rs3846662, an HMGCR SNP that regulates exon 13 skipping, was predicted to alter an HNRNPA1 binding motif. Yu et al. (2014) not only demonstrated that rs3846662 modulates HNRNPA1 binding, but also that sterol depletion of human hepatoma cell lines reduced HNRNPA1 mRNA levels, an effect that was reversed with sterol add-back. Overexpression of HNRNPA1 increased the ratio of HMGCR13(-) to total HMGCR transcripts by both directly increasing exon 13 skipping in an allele-related manner and specifically stabilizing the HMGCR13(-) transcript. Importantly, HNRNPA1 overexpression also diminished HMGCR enzyme activity, enhanced LDL-cholesterol uptake, and increased cellular apolipoprotein B (APOB; 107730). A SNP associated with HNRNPA1 exon 8 alternative splicing, rs1920045, was also associated with smaller statin-induced reduction in total cholesterol in 2 independent clinical trials. Yu et al. (2014) concluded that HNRNPA1 plays a role in the variation of cardiovascular disease risk and statin response.
Autosomal Recessive Limb-Girdle Muscular Dystrophy 28
In 6 affected members of a large consanguineous Bedouin kindred with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375), Yogev et al. (2023) identified a homozygous missense mutation in the HMGCR gene (G822D; 142910.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional studies in SH-SY5Y cells transfected with the mutation showed that the mutant protein had normal subcellular localization, but decreased activity. There was a 69% reduction in V(max) and a 65% increase in K(m) for the HMG-CoA substrate compared to controls. In addition, the catalytic pocket of the mutant protein had a very low affinity for pravastatin. These findings were consistent with a partial loss-of-function effect. Mevalonate levels were low in 1 of the patients studied; she showed clinical improvement after treatment with mevalonolactone.
In 9 patients from 5 unrelated families with LGMDR28, Morales-Rosado et al. (2023) identified homozygous or compound heterozygous mutations in the HMGCR gene (see, e.g., 142910.0004-142910.0009). The patients were ascertained through online matchmaking and collaborative efforts after exome sequencing identified the mutations. The mutations segregated with the disorder in the families and were absent from or present at low frequencies in the gnomAD database. There were 7 missense mutations, 1 splice site mutation, and 1 in-frame deletion. In vitro functional expression studies of 3 of the missense mutations (R443Q, Y792C, and D623N) showed that they caused variably reduced HMGCR enzyme activity and protein stability. There were no apparent genotype/phenotype correlations, but the authors noted that phenotypic variability may result from the degree of hypomorphic impairment resulting from the combined effect of the biallelic variants.
In a study of cholesterol reduction effects of statin therapy among 1,536 individuals, Chasman et al. (2004) found that 2 common and tightly linked SNPs in the gene encoding HMG-CoA reductase, the target enzyme that is inhibited by pravastatin, were significantly associated with reduced efficacy of pravastatin therapy in reducing cholesterol level (see 620410). The SNPs, designated SNP12 and SNP29, are located in introns 5 and 15, respectively, and define a haplotype designated haplotype 7. Compared with individuals homozygous for the major allele of 1 of the SNPs, individuals with a single copy of the minor allele had a 22% smaller reduction in total cholesterol. The 2 SNPs showed a linkage disequilibrium of 0.90; the prevalence of heterozygotes for both was 6.7%. SNP12 and SNP29 correspond to rs17244841 and rs17238540, respectively.
Kathiresan et al. (2008) replicated the association of rs12654264 (c.300A-T) of the HMGCR gene with LDL cholesterol levels (LDLCQ3; 620410) in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study (p = 4 x 10(-4)).
In 6 affected members of a large consanguineous Bedouin kindred with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375), Yogev et al. (2023) identified a homozygous c.2465G-A transition (c.2465G-A, NM_000859.3) in the HMGCR gene, resulting in a gly822-to-asp (G822D) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in large databases or among 210 ethnically matched controls. In vitro functional studies in SH-SY5Y cells transfected with the mutation showed that the mutant protein had normal subcellular localization, but decreased activity. There was a 69% reduction in V(max) and a 65% increase in K(m) for the HMG-CoA substrate compared to controls. In addition, the catalytic pocket of the mutant protein had a very low affinity for pravastatin. These findings were consistent with a partial loss-of-function effect. The patients had onset of progressive proximal muscle weakness affecting the upper and lower limbs in the fourth decade. Older patients lost ambulation and developed respiratory insufficiency. Mevalonate levels were low in 1 of the patients studied; she showed clinical improvement after treatment with mevalonolactone.
In 3 brothers (family 1) with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375), Morales-Rosado et al. (2023) identified compound heterozygous missense mutations in the HMGCR gene: a c.1328G-A transition (c.1328G-A, NM_000859.2) in exon 11, resulting in an arg443-to-gln (R443Q) substitution, and a c.1867G-A transition in exon 14, resulting in an asp623-to-asn (D623N; 142910.0005) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred at highly conserved residues: R443Q in the linker region and D623N in the catalytic domain. The R443Q mutation was found once in gnomAD (1 in 251,244 alleles), whereas D623N was absent from gnomAD. In vitro studies showed that both mutations reduced enzymatic activity compared to wildtype: R443Q had 1.16% residual activity, and D623N had 44.64% residual activity. In addition, the R443Q mutant protein showed reduced thermal stability and was 20% larger than the wildtype protein. The patients, who were in their late thirties, had onset of slowly progressive proximal muscle weakness in the first decade.
For discussion of the c.1867G-A transition (c.1867G-A, NM_000859.2) in the HMGCR gene, resulting in an asp623-to-asn (D623N) substitution, that was found in compound heterozygous state in 3 brothers with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375) by Morales-Rosado et al. (2023), see 142910.0004.
In 2 sibs (family 2) with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375), Morales-Rosado et al. (2023) identified compound heterozygous mutations in the HMGCR gene: a c.2375A-G transition (c.2375A-G, NM_000859.2) in exon 18, resulting in a tyr792-to-cys (Y792C) substitution at a highly conserved residue in the catalytic domain, and an A-to-G transition in intron 4 (c.365+4A-G; 142910.0007), predicted to result in a splicing defect. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the gnomAD database. In vitro studies showed that the Y792C mutation reduced enzymatic activity to about 25.42% compared to wildtype; functional studies of the splice site mutation were not performed. The patients, who were 19 and 22 years of age, had onset of symptoms in the first decade and followed a rapidly progressive disease course; 1 was wheelchair-bound.
For discussion of the A-to-G transition in intron 4 (c.365+4A-G, NM_000859.2) of the HMGCR gene, predicted to result in a splicing defect, that was found in compound heterozygous state in 2 sibs with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375) by Morales-Rosado et al. (2023), see 142910.0006.
In 2 sibs, born of consanguineous parents (family 4), with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375), Morales-Rosado et al. (2023) identified compound heterozygous mutations in the HMGCR gene: a c.1327C-T transition (c.1327C-T, NM_000859.2) in exon 11, resulting in an arg443-to-trp (R443W) substitution at a conserved residue in the linker domain, and a 3-bp in-frame deletion (c.1517_1519delCTT; 142910.0009) in exon 12, resulting in the deletion of conserved residue ser508 (Ser508del) in the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. The patients had onset of symptoms in the first years of life and showed a rapidly progressive disease course, resulting in death at 10 and 8 years of age.
For discussion of the 3-bp in-frame deletion (c.1517_1519delCTT, NM_000859.2) in exon 12 of the HMGCR gene, resulting in the deletion of conserved residue ser508 (Ser508del) in the catalytic domain, that was found in compound heterozygous state in 2 sibs with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375) by Morales-Rosado et al. (2023), see 142910.0008.
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