The HADH gene is located on the 4th chromosome, with its specific location being identified as 4q22-q26. The gene has 10 exons.[7] The HADH gene encodes a 34.3 kDa protein that has 314 amino acids and 124 observed peptides.[8][9]
Functionedit
This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids.[7]
Clinical significanceedit
Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia.[10] A deficiency is associated with 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Mutations also cause 3-hydroxyacyl-CoA dehydrogenase deficiency. There are a wide variety of mutations that have been identified to cause this disease. Among them are missense mutations (A40T, P258L, D57G, Y226H) and nonsense mutations (R236X) in the protein, and splicing mutations (261+1G>A, 710-2A>G) and some small deletions (587delC) in the cDNA.[11] One mutation, 636+471G>T in the HADH gene, was shown to create a cryptic splice donor site and an out-of-frame pseudoexon.[12] Most of the described cases have homozygous mutations. This disease has fairly homogenous clinical presentation across cases. The symptoms first appear in early life, between 1.5 hours post birth and 3 years of age, and the most common symptoms are hypoglycemia and seizures/convulsions directly related to the hypoglycemia. There are other clinical presentations that have been identified, namely: myoglobinuria, dicarboxylic aciduria, feeding difficulties in infancy, muscular hypotonia, hepatic steatosis, growth delay, hypertrophic cardiomyopathy, dilated cardiomyopathy, hepatic necrosis, and fulminant hepatic failure. The disorder may be diagnosed by either the analysis of the molecular genetics of the individual, or by detection of abnormal metabolite levels in blood and/or plasma. Individuals with this deficiency have an elevated amount of 3-hydroxyglutarate excreted through the urine; a heightened level of C4-OH acylcarnitine in the blood plasma is also a characteristic of this FAO disorder. Most documented cases thus far have shown that individuals are responsive to diazoxide treatment, and highlight the need for diagnosis and treatment administration as early as possible in order to correct hypoglycemia and avoid irreversible brain damage.[11]
Interactionsedit
HADH has been shown to interact with Vpr, such that HIV-1 Vpr regulates mitochondrial respiration and enhances the activity of hydroxyacyl-CoA dehydrogenase (HADH) through PPARbeta/delta.[13]
^ abcGRCh38: Ensembl release 89: ENSG00000138796 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000027984 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Craig I, Tolley E, Bobrow M (1976). "A preliminary analysis of the segregation of human hydroxyacyl coenzyme A dehydrogenase in human-mouse somatic cell hybrids". Cytogenetics and Cell Genetics. 16 (1–5): 114–7. doi:10.1159/000130568. PMID 975867.
^Yang SY, He XY, Schulz H (Oct 2005). "3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease". The FEBS Journal. 272 (19): 4874–83. doi:10.1111/j.1742-4658.2005.04911.x. PMID 16176262. S2CID 45683141.
^Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC4076475. PMID 23965338.
^. Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2015-09-24. Retrieved 2015-03-23.
^Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njølstad PR, Jellum E, Søvik O (Jan 2004). "Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation". Diabetes. 53 (1): 221–7. doi:10.2337/diabetes.53.1.221. PMID 14693719.
^ abMartins E, Cardoso ML, Rodrigues E, Barbot C, Ramos A, Bennett MJ, Teles EL, Vilarinho L (Jun 2011). "Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: the clinical relevance of an early diagnosis and report of four new cases". Journal of Inherited Metabolic Disease. 34 (3): 835–42. doi:10.1007/s10545-011-9287-7. PMID 21347589. S2CID 36618116.
^Flanagan SE, Xie W, Caswell R, Damhuis A, Vianey-Saban C, Akcay T, Darendeliler F, Bas F, Guven A, Siklar Z, Ocal G, Berberoglu M, Murphy N, O'Sullivan M, Green A, Clayton PE, Banerjee I, Clayton PT, Hussain K, Weedon MN, Ellard S (Jan 2013). "Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation". American Journal of Human Genetics. 92 (1): 131–6. doi:10.1016/j.ajhg.2012.11.017. PMC3542457. PMID 23273570.
^Shrivastav S, Zhang L, Okamoto K, Lee H, Lagranha C, Abe Y, Balasubramanyam A, Lopaschuk GD, Kino T, Kopp JB (Sep 2013). "HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity". Molecular Endocrinology. 27 (9): 1564–76. doi:10.1210/me.2012-1370. PMC3753422. PMID 23842279.
External linksedit
GeneReviews/NCBI/NIH/UW entry on Familial Hyperinsulinism
Overview of all the structural information available in the PDB for UniProt: Q16836 (Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial) at the PDBe-KB.
hydroxyacyl, coenzyme, dehydrogenase, hadh, redirects, here, hydroxyacyl, dehydrogenase, trifunctional, multienzyme, complex, subunit, alpha, hadha, hadh, enzyme, which, humans, encoded, hadh, gene, hadhavailable, structurespdbortholog, search, pdbe, rcsblist,. HADH redirects here For hydroxyacyl CoA dehydrogenase trifunctional multienzyme complex subunit alpha see HADHA Hydroxyacyl Coenzyme A dehydrogenase HADH is an enzyme which in humans is encoded by the HADH gene 5 6 HADHAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes1F0Y 1F12 1F14 1F17 1IL0 1LSJ 1LSO 1M75 1M76 2HDH 3HAD 3RQSIdentifiersAliasesHADH HAD HADH1 HADHSC HCDH HHF4 MSCHAD SCHAD Hydroxyacyl Coenzyme A dehydrogenase hydroxyacyl CoA dehydrogenaseExternal IDsOMIM 601609 MGI 96009 HomoloGene 55888 GeneCards HADHGene location Human Chr Chromosome 4 human 1 Band4q25Start107 989 714 bp 1 End108 035 241 bp 1 Gene location Mouse Chr Chromosome 3 mouse 2 Band3 3 G3Start131 027 068 bp 2 End131 065 750 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inislet of Langerhansright ventriclethoracic diaphragmkidney tubulevastus lateralis musclebody of tonguejejunal mucosagastrocnemius musclerectumduodenumTop expressed inPaneth cellcondylemedullary collecting ductbrown adipose tissuecumulus cellfossarenal corpuscleleft lobe of liverendocardial cushionatrioventricular valveMore reference expression dataBioGPSn aGene ontologyMolecular functionoxidoreductase activity 3 hydroxyacyl CoA dehydrogenase activity NAD bindingCellular componentcytoplasm mitochondrial matrix mitochondrion nucleoplasmBiological processresponse to insulin response to hormone fatty acid beta oxidation negative regulation of insulin secretion response to activity fatty acid metabolic process lipid metabolism positive regulation of cold induced thermogenesisSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez303315107EnsemblENSG00000138796ENSMUSG00000027984UniProtQ16836Q61425RefSeq mRNA NM 001184705NM 005327NM 001331027NM 008212RefSeq protein NP 001171634NP 001317956NP 005318NP 032238Location UCSC Chr 4 107 99 108 04 MbChr 3 131 03 131 07 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Structure 2 Function 3 Clinical significance 4 Interactions 5 See also 6 References 7 External linksStructure editThe HADH gene is located on the 4th chromosome with its specific location being identified as 4q22 q26 The gene has 10 exons 7 The HADH gene encodes a 34 3 kDa protein that has 314 amino acids and 124 observed peptides 8 9 Function editThis gene is a member of the 3 hydroxyacyl CoA dehydrogenase gene family The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight chain 3 hydroxyacyl CoAs as part of the beta oxidation pathway Its enzymatic activity is highest with medium chain length fatty acids 7 Clinical significance editMutations in this gene cause one form of familial hyperinsulinemic hypoglycemia 10 A deficiency is associated with 3 hydroxyacyl coenzyme A dehydrogenase deficiency Mutations also cause 3 hydroxyacyl CoA dehydrogenase deficiency There are a wide variety of mutations that have been identified to cause this disease Among them are missense mutations A40T P258L D57G Y226H and nonsense mutations R236X in the protein and splicing mutations 261 1G gt A 710 2A gt G and some small deletions 587delC in the cDNA 11 One mutation 636 471G gt T in the HADH gene was shown to create a cryptic splice donor site and an out of frame pseudoexon 12 Most of the described cases have homozygous mutations This disease has fairly homogenous clinical presentation across cases The symptoms first appear in early life between 1 5 hours post birth and 3 years of age and the most common symptoms are hypoglycemia and seizures convulsions directly related to the hypoglycemia There are other clinical presentations that have been identified namely myoglobinuria dicarboxylic aciduria feeding difficulties in infancy muscular hypotonia hepatic steatosis growth delay hypertrophic cardiomyopathy dilated cardiomyopathy hepatic necrosis and fulminant hepatic failure The disorder may be diagnosed by either the analysis of the molecular genetics of the individual or by detection of abnormal metabolite levels in blood and or plasma Individuals with this deficiency have an elevated amount of 3 hydroxyglutarate excreted through the urine a heightened level of C4 OH acylcarnitine in the blood plasma is also a characteristic of this FAO disorder Most documented cases thus far have shown that individuals are responsive to diazoxide treatment and highlight the need for diagnosis and treatment administration as early as possible in order to correct hypoglycemia and avoid irreversible brain damage 11 Interactions editHADH has been shown to interact with Vpr such that HIV 1 Vpr regulates mitochondrial respiration and enhances the activity of hydroxyacyl CoA dehydrogenase HADH through PPARbeta delta 13 See also edit3 hydroxyacyl CoA dehydrogenase hydroxyacyl CoA dehydrogenase 3 ketoacyl CoA thiolase enoyl CoA hydratase trifunctional protein alpha subunitReferences edit a b c GRCh38 Ensembl release 89 ENSG00000138796 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000027984 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Craig I Tolley E Bobrow M 1976 A preliminary analysis of the segregation of human hydroxyacyl coenzyme A dehydrogenase in human mouse somatic cell hybrids Cytogenetics and Cell Genetics 16 1 5 114 7 doi 10 1159 000130568 PMID 975867 Yang SY He XY Schulz H Oct 2005 3 Hydroxyacyl CoA dehydrogenase and short chain 3 hydroxyacyl CoA dehydrogenase in human health and disease The FEBS Journal 272 19 4874 83 doi 10 1111 j 1742 4658 2005 04911 x PMID 16176262 S2CID 45683141 a b Entrez Gene HADH Zong NC Li H Li H Lam MP Jimenez RC Kim CS Deng N Kim AK Choi JH Zelaya I Liem D Meyer D Odeberg J Fang C Lu HJ Xu T Weiss J Duan H Uhlen M Yates JR Apweiler R Ge J Hermjakob H Ping P Oct 2013 Integration of cardiac proteome biology and medicine by a specialized knowledgebase Circulation Research 113 9 1043 53 doi 10 1161 CIRCRESAHA 113 301151 PMC 4076475 PMID 23965338 Hydroxyacyl coenzyme A dehydrogenase mitochondrial Cardiac Organellar Protein Atlas Knowledgebase COPaKB Archived from the original on 2015 09 24 Retrieved 2015 03 23 Molven A Matre GE Duran M Wanders RJ Rishaug U Njolstad PR Jellum E Sovik O Jan 2004 Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation Diabetes 53 1 221 7 doi 10 2337 diabetes 53 1 221 PMID 14693719 a b Martins E Cardoso ML Rodrigues E Barbot C Ramos A Bennett MJ Teles EL Vilarinho L Jun 2011 Short chain 3 hydroxyacyl CoA dehydrogenase deficiency the clinical relevance of an early diagnosis and report of four new cases Journal of Inherited Metabolic Disease 34 3 835 42 doi 10 1007 s10545 011 9287 7 PMID 21347589 S2CID 36618116 Flanagan SE Xie W Caswell R Damhuis A Vianey Saban C Akcay T Darendeliler F Bas F Guven A Siklar Z Ocal G Berberoglu M Murphy N O Sullivan M Green A Clayton PE Banerjee I Clayton PT Hussain K Weedon MN Ellard S Jan 2013 Next generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation American Journal of Human Genetics 92 1 131 6 doi 10 1016 j ajhg 2012 11 017 PMC 3542457 PMID 23273570 Shrivastav S Zhang L Okamoto K Lee H Lagranha C Abe Y Balasubramanyam A Lopaschuk GD Kino T Kopp JB Sep 2013 HIV 1 Vpr enhances PPARb d mediated transcription increases PDK4 expression and reduces PDC activity Molecular Endocrinology 27 9 1564 76 doi 10 1210 me 2012 1370 PMC 3753422 PMID 23842279 External links editGeneReviews NCBI NIH UW entry on Familial Hyperinsulinism Overview of all the structural information available in the PDB for UniProt Q16836 Hydroxyacyl coenzyme A dehydrogenase mitochondrial at the PDBe KB This article incorporates text from the United States National Library of Medicine which is in the public domain Retrieved from https en wikipedia org w index php title Hydroxyacyl Coenzyme A dehydrogenase amp oldid 1212894819, wikipedia, wiki, book, books, library,
