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Gene Review

HADHA  -  hydroxyacyl-CoA dehydrogenase/3-ketoacyl...

Homo sapiens

Synonyms: 78 kDa gastrin-binding protein, ECHA, GBP, HADH, LCEH, ...
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Disease relevance of HADHA

  • Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency [1].
  • Our results demonstrate that mutations in the LCHAD domain of the trifunctional protein alpha subunit in affected offspring are associated with maternal acute fatty liver of pregnancy [2].
  • We used single-stranded conformation variance analysis of the exons of the human LCHAD (alpha subunit) gene to determine the molecular basis of LCHAD deficiency in three families with children presenting with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome) [2].
  • Screening this region with additional microsatellite markers revealed that the adjacent marker D2S1374 was also significantly associated with obstetric cholestasis, whereas no association was found with the markers located in the vicinity of the hydroxyacyl-CoA dehyrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit (HADHA) gene [3].
  • Is it HELLPful to consider the hanging LCHAD in pregnancy-associated liver disease [4]?

Psychiatry related information on HADHA


High impact information on HADHA


Chemical compound and disease context of HADHA


Biological context of HADHA


Anatomical context of HADHA

  • The retinal pigment epithelium (RPE) and the choriocapillaris are affected early in the retinopathy associated with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency [16].
  • Whole genome homozygosity mapping with 262 SNP markers mapped the disease gene to chromosome 5 where candidate genes Hadha and Hadhb, encoding the mitochondria trifunctional protein (MTP) alpha- and beta-subunits, respectively, are located [17].
  • BACKGROUND: The diagnosis of long-chain L-3-hydroxy-acyl-coenzyme A dehydrogenase (LCHAD) deficiency frequently requires the study of cultured fibroblasts [18].
  • CONCLUSIONS: Measurement of 3-OHFA excretion from LCHAD- or MTFP-deficient cell lines can be used as a diagnostic tool [18].
  • Furthermore, we measured the enzymatic activity of the VLCAD, LCHAD, and carnitine palmitoyl-CoA transferase 2 (CPT2) enzymes in different human fetal tissues [5].

Associations of HADHA with chemical compounds

  • The existing LCHAD primers, which produce a 640-bp amplicon (IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ: J Clin Invest 98:1028-1033, 1996), were modified to make them amenable to analysis of fragmented DNA obtained from microdissected formalin-fixed material [14].
  • Conversely, signaling by TP alpha S329A was insensitive to cicaprost stimulation whereas it was fully desensitized by NO/PKG signaling [19].
  • Signaling by TP alpha, but not TP beta, is subject to prostacyclin-induced desensitization mediated by direct protein kinase (PK) A phosphorylation where Ser329 represents the phosphotarget (Walsh, M. T., Foley, J. F., and Kinsella, B. T. (2000) J. Biol. Chem. 275, 20412-20423) [19].
  • The NO donor 3-morpholinosydnonimine, HCl (SIN-1) and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-Br-cGMP) functionally desensitized U46619-mediated calcium mobilization and inositol 1,4,5-trisphosphate generation by TP alpha whereas signaling by TP beta was unaffected by either agent [19].
  • Mutation of Ser(329) to Ala(329) within a consensus PKA site in TP alpha rendered the mutant TP alpha(S329A) insensitive to BW245C-mediated desensitization [20].

Other interactions of HADHA


Analytical, diagnostic and therapeutic context of HADHA


  1. Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency. Choi, J.H., Yoon, H.R., Kim, G.H., Park, S.J., Shin, Y.L., Yoo, H.W. Int. J. Mol. Med. (2007) [Pubmed]
  2. The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Sims, H.F., Brackett, J.C., Powell, C.K., Treem, W.R., Hale, D.E., Bennett, M.J., Gibson, B., Shapiro, S., Strauss, A.W. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  3. Maternal susceptibility locus for obstetric cholestasis maps to chromosome region 2p13 in Finnish patients. Heinonen, S., Eloranta, M.L., Heiskanen, J., Punnonen, K., Helisalmi, S., Mannermaa, A., Hiltunen, M. Scand. J. Gastroenterol. (2001) [Pubmed]
  4. Is it HELLPful to consider the hanging LCHAD in pregnancy-associated liver disease? Zucker, S.D. Gastroenterology (2003) [Pubmed]
  5. Long-chain fatty acid oxidation during early human development. Oey, N.A., den Boer, M.E., Wijburg, F.A., Vekemans, M., Augé, J., Steiner, C., Wanders, R.J., Waterham, H.R., Ruiter, J.P., Attié-Bitach, T. Pediatr. Res. (2005) [Pubmed]
  6. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a case example in developmental disabilities. Faulkner, M.S. Journal of pediatric nursing. (1999) [Pubmed]
  7. Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene. IJlst, L., Ruiter, J.P., Hoovers, J.M., Jakobs, M.E., Wanders, R.J. J. Clin. Invest. (1996) [Pubmed]
  8. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Wilcken, B., Leung, K.C., Hammond, J., Kamath, R., Leonard, J.V. Lancet (1993) [Pubmed]
  9. Antiproliferative gastrin/cholecystokinin receptor antagonists target the 78-kDa gastrin-binding protein. Baldwin, G.S. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  10. Bile acylcarnitine profiles in pediatric liver disease do not interfere with the diagnosis of long-chain fatty acid oxidation defects. Fuda, F., Narayan, S.B., Squires, R.H., Bennett, M.J. Clin. Chim. Acta (2006) [Pubmed]
  11. Genes for the human mitochondrial trifunctional protein alpha- and beta-subunits are divergently transcribed from a common promoter region. Orii, K.E., Orii, K.O., Souri, M., Orii, T., Kondo, N., Hashimoto, T., Aoyama, T. J. Biol. Chem. (1999) [Pubmed]
  12. Fluorescence in situ hybridization mapping of the alpha and beta subunits (HADHA and HADHB) of human mitochondrial fatty acid beta-oxidation multienzyme complex to 2p23 and their evolution. Aoyama, T., Wakui, K., Orii, K.E., Hashimoto, T., Fukushima, Y. Cytogenet. Cell Genet. (1997) [Pubmed]
  13. Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene. Das, A.M., Illsinger, S., Lücke, T., Hartmann, H., Ruiter, J.P., Steuerwald, U., Waterham, H.R., Duran, M., Wanders, R.J. Clin. Chem. (2006) [Pubmed]
  14. Absence of the G1528C (E474Q) mutation in the alpha-subunit of the mitochondrial trifunctional protein in women with acute fatty liver of pregnancy. Maitra, A., Domiati-Saad, R., Yost, N., Cunningham, G., Rogers, B.B., Bennett, M.J. Pediatr. Res. (2002) [Pubmed]
  15. Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene. Zhang, Q.X., Baldwin, G.S. Biochim. Biophys. Acta (1994) [Pubmed]
  16. Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Tyni, T., Paetau, A., Strauss, A.W., Middleton, B., Kivelä, T. Pediatr. Res. (2004) [Pubmed]
  17. ENU mutagenesis identifies mice with cardiac fibrosis and hepatic steatosis caused by a mutation in the mitochondrial trifunctional protein {beta}-subunit. Kao, H.J., Cheng, C.F., Chen, Y.H., Hung, S.I., Huang, C.C., Millington, D., Kikuchi, T., Wu, J.Y., Chen, Y.T. Hum. Mol. Genet. (2006) [Pubmed]
  18. Accumulation of free 3-hydroxy fatty acids in the culture media of fibroblasts from patients deficient in long-chain l-3-hydroxyacyl-CoA dehydrogenase: a useful diagnostic aid. Jones, P.M., Moffitt, M., Joseph, D., Harthcock, P.A., Boriack, R.L., Ibdah, J.A., Strauss, A.W., Bennett, M.J. Clin. Chem. (2001) [Pubmed]
  19. The alpha, but not the beta, isoform of the human thromboxane A2 receptor is a target for nitric oxide-mediated desensitization. Independent modulation of Tp alpha signaling by nitric oxide and prostacyclin. Reid, H.M., Kinsella, B.T. J. Biol. Chem. (2003) [Pubmed]
  20. Prostaglandin D(2) receptor-mediated desensitization of the alpha isoform of the human thromboxane A(2) receptor. Foley, J.F., Kelley, L.P., Kinsella, B.T. Biochem. Pharmacol. (2001) [Pubmed]
  21. Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency. Orii, K.E., Aoyama, T., Wakui, K., Fukushima, Y., Miyajima, H., Yamaguchi, S., Orii, T., Kondo, N., Hashimoto, T. Hum. Mol. Genet. (1997) [Pubmed]
  22. Identification of a Novel Single Nucleotide Polymorphism of HADHA Gene at a Referred Primer-binding Site During Pre-diagnostic Tests for Preimplantation Genetic Diagnosis. Lee, H.S., Choi, H.W., Lim, C.K., Koong, M.K., Kang, I.S., Yoo, H.W., Choi, J.H., Jun, J.H. J. Korean Med. Sci. (2006) [Pubmed]
  23. Hypoparathyroidism in a patient with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency caused by the G1528C mutation. Tyni, T., Rapola, J., Palotie, A., Pihko, H. J. Pediatr. (1997) [Pubmed]
  24. Acyl-CoA dehydrogenase 9 (ACAD 9) is the long-chain acyl-CoA dehydrogenase in human embryonic and fetal brain. Oey, N.A., Ruiter, J.P., Ijlst, L., Attie-Bitach, T., Vekemans, M., Wanders, R.J., Wijburg, F.A. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  25. Mitochondrial fatty acid beta-oxidation in the retinal pigment epithelium. Tyni, T., Johnson, M., Eaton, S., Pourfarzam, M., Andrews, R., Turnbull, D.M. Pediatr. Res. (2002) [Pubmed]
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