.. _HMGCS2: HMGCS2 ^^^^^^ .. contents:: :local: General Information ******************* :Full gene name: 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) :Entrez Gene ID: 3158 :Location: 1p13-p12 :Synonyms: :Type: protein-coding User SNPs ********* SNPs given by the user that are near or inside this gene: +------------+---------------+-----------+ | SNP | Distance (bp) | Direction | +============+===============+===========+ | rs10923931 | 206404 | upstream | +------------+---------------+-----------+ .. _HMGCS2 Gene summary: NCBI Summary ************ The protein encoded by this gene belongs to the HMG-CoA synthase family. It is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting. Mutations in this gene are associated with HMG-CoA synthase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009] .. _OMIM ID 600234 : http://omim.org/entry/600234 .. _HMGCS2 OMIM Text: OMIM **** :OMIM ID: `OMIM ID 600234 `_ **Allelic Variants (Selected Examples)** .0001 MITOCHONDRIAL HMG-CoA SYNTHASE DEFICIENCY In a patient with HMG-CoA synthase deficiency (605911) described by Thompson et al. (1997), Bouchard et al. (2001) identified a T-to-C substitution at nucleotide 520 of the HMGCS2 gene, resulting in a phenylalanine-to-leucine substitution at codon 174 (F174L). This mutation was found in homozygosity; both parents were carriers. When expressed in bacteria, the F174L mutation resulted in a mitochondrial HMG-CoA synthase polypeptide with no detectable activity. .0002 MITOCHONDRIAL HMG-CoA SYNTHASE DEFICIENCY In a patient with HMG-CoA synthase deficiency (605911) described by Morris et al. (1998), Bouchard et al. (2001) identified a C-to-T transition at nucleotide 1270 of the HMGCS2 gene, resulting in an arg-to-ter substitution at codon 424 (R424X). This patient was a genetic compound for this mutation; the second mutation was not characterized. .0003 MITOCHONDRIAL HMG-CoA SYNTHASE DEFICIENCY Aledo et al. (2001) described compound heterozygosity for 2 mutations in the HMGCS2 gene in a patient with HMG-CoA synthase deficiency (605911). A heterozygous G-to-A transition at nucleotide 634 in exon 3, inherited from the father, was predicted to cause a gly212-to-arg (G212R) amino acid substitution. In exon 9 of the patient and his mother, a heterozygous G-to-A transition at nucleotide 1499 was identified and predicted to cause an arg500-to-his (R500H; 600234.0004) amino acid substitution. The affected boy presented at the age of 11 months with acute hypoglycemic coma and respiratory arrest after a 2-day history of gastroenteritis, vomiting, and poor food intake. In addition to low blood \ ``glucose``\ , elevated transaminases and lactate dehydrogenase were found at admission. During a monitored fasting test, massive elevation of plasma free fatty acids without concomitant elevation of total plasma ketones was observed. The patient was placed on supplementary carnitine and the family was advised to avoid fasting for more than 8 hours and to administer a caloric drink at around midnight. Under this regimen, there were no subsequent hypoglycemic episodes, and the child at 4 years of age was developing normally with no residual neurologic impairment. .0004 MITOCHONDRIAL HMG-CoA SYNTHASE DEFICIENCY See 600234.0003 and Aledo et al. (2001). .0005 MITOCHONDRIAL HMG-CoA SYNTHASE DEFICIENCY In 2 sisters with mitochondrial HMG-CoA synthase deficiency (605911), the offspring of healthy unrelated Caucasian parents, Wolf et al. (2003) identified compound heterozygosity for 2 mutations in exon 2 of the HMGCS2 gene: a 160G-A transition resulting in a val54-to-met (V54M) substitution, and 500A-G transition resulting in a tyr167-to-cys (Y167C) substitution (600234.0006). Carrier status was confirmed in both parents. .0006 MITOCHONDRIAL HMG-CoA SYNTHASE DEFICIENCY See 600234.0005 and Wolf et al. (2003). The Y167C mutation occurs in the catalytic domain of the HMGCS2 enzyme. .. _HMGCS2 Phenotype: NCBI Phenotypes *************** * Gene Reviews * GTR * mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency * OMIM .. _HMGCS2 GO Term: Gene Ontology ************* * ketone body biosynthetic process * cellular response to organic cyclic compound * cellular response to glucocorticoid stimulus * lung development * response to prostaglandin F stimulus * multicellular organismal response to stress * response to starvation * mitochondrion * cellular response to fatty acid * response to monosaccharide stimulus * cellular response to amino acid stimulus * response to ethanol * midgut development * response to linoleic acid * small molecule metabolic process * adipose tissue development * response to metal ion * response to temperature stimulus * response to nutrient * hydroxymethylglutaryl-CoA synthase activity * response to triglyceride * response to growth hormone stimulus * liver development * cellular response to \ ``insulin``\ stimulus * brain development * isoprenoid biosynthetic process * response to testosterone stimulus * response to drug * response to glucagon stimulus * response to cAMP * mitochondrial inner membrane * mitochondrial matrix * cellular lipid metabolic process * kidney development * cellular response to lipopolysaccharide * cholesterol biosynthetic process * cellular ketone body metabolic process .. _HMGCS2 Pathway: KEGG Pathways ************* * `Valine, leucine and isoleucine degradation `_ * `Synthesis and degradation of ketone bodies `_ * `Butanoate metabolism `_ * `Metabolic pathways `_ * `Terpenoid backbone biosynthesis `_ * `PPAR signaling pathway `_ .. _HMGCS2 GeneRIF: GeneRIFs ******** * The authors report high-resolution crystal structures of the human cytosolic (hHMGCS1) and mitochondrial (hHMGCS2) isoforms in binary product complexes. [`PMID 20346956`_] * Affinity Capture-MS [`PMID 20618440`_] * Observational study of gene-disease association. (HuGE Navigator) [`PMID 20877624`_] * Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [`PMID 20628086`_] * An alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively, were detected. [`PMID 21952825`_] * Ketogenesis is an undesirable metabolic characteristic of the proliferating cell, which is down-regulated through c-Myc-mediated repression of the key metabolic gene HMGCS2. [`PMID 16940161`_] * Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression [`PMID 21502324`_] * Affinity Capture-MS [`PMID 21906983`_] * Observational study and genome-wide association study of gene-disease association. (HuGE Navigator) [`PMID 20549515`_] .. _PMID 20346956: http://www.ncbi.nlm.nih.gov/pubmed/20346956 .. _PMID 20618440: http://www.ncbi.nlm.nih.gov/pubmed/20618440 .. _PMID 20877624: http://www.ncbi.nlm.nih.gov/pubmed/20877624 .. _PMID 20628086: http://www.ncbi.nlm.nih.gov/pubmed/20628086 .. _PMID 21952825: http://www.ncbi.nlm.nih.gov/pubmed/21952825 .. _PMID 16940161: http://www.ncbi.nlm.nih.gov/pubmed/16940161 .. _PMID 21502324: http://www.ncbi.nlm.nih.gov/pubmed/21502324 .. _PMID 21906983: http://www.ncbi.nlm.nih.gov/pubmed/21906983 .. _PMID 20549515: http://www.ncbi.nlm.nih.gov/pubmed/20549515 .. _HMGCS2 Pubmed: PubMed Articles *************** *Recent articles:* * Puisac B et al. "Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway." Mol Biol Rep. 2012 Apr;39(4):4777-85. `PMID 21952825`_ * Kim W et al. "Systematic and quantitative assessment of the ubiquitin-modified proteome." Mol Cell. 2011 Oct 21;44(2):325-40. `PMID 21906983`_ * Vilà-Brau A et al. "Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression in HepG2 cell line." J Biol Chem. 2011 Jun 10;286(23):20423-30. `PMID 21502324`_ * Bailey SD et al. "Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study." Diabetes Care. 2010 Oct;33(10):2250-3. `PMID 20628086`_ * Hendrickson SL et al. "Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression." PLoS One. 2010 Sep 21;5(9):e12862. `PMID 20877624`_ * Feng T et al. "Genome-wide searching of rare genetic variants in WTCCC data." Hum Genet. 2010 Sep;128(3):269-80. `PMID 20549515`_ * Pozuelo-Rubio M et al. "Proteomic and biochemical analysis of 14-3-3-binding proteins during C2-ceramide-induced apoptosis." FEBS J. 2010 Aug;277(16):3321-42. `PMID 20618440`_ * Shafqat N et al. "Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design." J Mol Biol. 2010 May 14;398(4):497-506. `PMID 20346956`_ * Talmud PJ et al. "Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip." Am J Hum Genet. 2009 Nov;85(5):628-42. `PMID 19913121`_ * Lu Y et al. "Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations." J Lipid Res. 2008 Dec;49(12):2582-9. `PMID 18660489`_ .. _PMID 20628086: http://www.ncbi.nlm.nih.gov/pubmed/20628086 .. _PMID 19913121: http://www.ncbi.nlm.nih.gov/pubmed/19913121 .. _PMID 20618440: http://www.ncbi.nlm.nih.gov/pubmed/20618440 .. _PMID 20346956: http://www.ncbi.nlm.nih.gov/pubmed/20346956 .. _PMID 18660489: http://www.ncbi.nlm.nih.gov/pubmed/18660489 .. _PMID 20877624: http://www.ncbi.nlm.nih.gov/pubmed/20877624 .. _PMID 21952825: http://www.ncbi.nlm.nih.gov/pubmed/21952825 .. _PMID 21502324: http://www.ncbi.nlm.nih.gov/pubmed/21502324 .. _PMID 21906983: http://www.ncbi.nlm.nih.gov/pubmed/21906983 .. _PMID 20549515: http://www.ncbi.nlm.nih.gov/pubmed/20549515 *Top Pubmed articles linked to gene HMGCS2 matching any search term:* * Naeem A et al. "Role of metabolic and cellular proliferation genes in ruminal development in response to enhanced plane of nutrition in neonatal Holstein calves." J Dairy Sci. 2012 Apr;95(4):1807-20. `PMID 22459829`_ * Steele MA et al. "Rumen epithelial adaptation to ruminal acidosis in lactating cattle involves the coordinated expression of insulin-like growth factor-binding proteins and a cholesterolgenic enzyme." J Dairy Sci. 2012 Jan;95(1):318-27. `PMID 22192211`_ * Zhang D et al. "Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes." Am J Physiol Endocrinol Metab. 2011 Feb;300(2):E287-95. `PMID 20959534`_ * Langley-Evans SC et al. "Protein restriction in the pregnant mouse modifies fetal growth and pulmonary development: role of fetal exposure to {beta}-hydroxybutyrate." Exp Physiol. 2011 Feb;96(2):203-15. `PMID 20851857`_ * Bailey SD et al. "Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study." Diabetes Care. 2010 Oct;33(10):2250-3. `PMID 20628086`_ * Feng T et al. "Genome-wide searching of rare genetic variants in WTCCC data." Hum Genet. 2010 Sep;128(3):269-80. `PMID 20549515`_ * Wentz AE et al. "Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment." J Biol Chem. 2010 Aug 6;285(32):24447-56. `PMID 20529848`_ * Kostiuk MA et al. "Palmitoylation of ketogenic enzyme HMGCS2 enhances its interaction with PPARalpha and transcription at the Hmgcs2 PPRE." FASEB J. 2010 Jun;24(6):1914-24. `PMID 20124434`_ * van Dorland HA et al. "Variation in hepatic regulation of metabolism during the dry period and in early lactation in dairy cows." J Dairy Sci. 2009 May;92(5):1924-40. `PMID 19389950`_ * Nakamura K et al. "Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver." J Biol Chem. 2007 Mar 30;282(13):9768-76. `PMID 17267396`_ * Nadal A et al. "Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1." Biochem J. 2002 Aug 15;366(Pt 1):289-97. `PMID 12027802`_ * Robinson AM et al. "Physiological roles of ketone bodies as substrates and signals in mammalian tissues." Physiol Rev. 1980 Jan;60(1):143-87. `PMID 6986618`_ .. _PMID 12027802: http://www.ncbi.nlm.nih.gov/pubmed/12027802 .. _PMID 20529848: http://www.ncbi.nlm.nih.gov/pubmed/20529848 .. _PMID 20959534: http://www.ncbi.nlm.nih.gov/pubmed/20959534 .. _PMID 22192211: http://www.ncbi.nlm.nih.gov/pubmed/22192211 .. _PMID 19389950: http://www.ncbi.nlm.nih.gov/pubmed/19389950 .. _PMID 17267396: http://www.ncbi.nlm.nih.gov/pubmed/17267396 .. _PMID 22459829: http://www.ncbi.nlm.nih.gov/pubmed/22459829 .. _PMID 20628086: http://www.ncbi.nlm.nih.gov/pubmed/20628086 .. _PMID 20851857: http://www.ncbi.nlm.nih.gov/pubmed/20851857 .. _PMID 6986618: http://www.ncbi.nlm.nih.gov/pubmed/6986618 .. _PMID 20124434: http://www.ncbi.nlm.nih.gov/pubmed/20124434 .. _PMID 20549515: http://www.ncbi.nlm.nih.gov/pubmed/20549515