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

• In this study, using in situ hybridization of the VLCAD and the LCHAD mRNA, we report on the expression of genes involved in the mitochondrial oxidation of long-chain fatty acids during early human development [5].
• A case example of a preschooler with LCHAD deficiency is presented to show the complexity of this disorder and resultant developmental disabilities [6].

High impact information on HADHA

• Mitochondrial trifunctional protein (MTP) is a recently identified enzyme involved in mitochondrial beta-oxidation, harboring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain 3-ketothiolase activity [7].
• The finding of an 87% allele frequency of the G1528C mutation in 34 LCHAD deficient patients makes this a valuable test for prenatal diagnosis [7].
• 6 of the babies had long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency, and each of the pregnancies was complicated by features such as fatty liver and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome [8].
• This is in the LCHAD domain and substitutes glutamine for glutamic acid at position 474 of mature alpha subunit [2].
• Antiproliferative gastrin/cholecystokinin receptor antagonists target the 78-kDa gastrin-binding protein [9].

Chemical compound and disease context of HADHA

• Patients with long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency manifest hypoketotic hypoglycemia, hepatomegaly, hypotonia, lactic acidemia, acute renal failure, cardiomyopathy, and sudden death [1].
• RESULTS: The non-metabolic liver disease had no effect on the diagnostic value of bile acylcarnitine levels for detecting LCHAD deficiency [10].

Biological context of HADHA

• We isolated genomic clones, including 5' flanking regions, for HADHA and HADHB [11].
• We analyzed the localization of each of these two genes (HADHA and HADHB) by in situ hybridization and found that both can be assigned to human chromosome band 2p23 [12].
• At present, 2 different biochemical phenotypes of defects in the mitochondrial trifunctional protein complex are known: isolated LCHAD deficiency and generalized MTP deficiency, with decreased activities of all 3 enzymes [13].
• We retrospectively examined a series of 10 women with pregnancies complicated by AFLP to determine the prevalence of the common LCHAD mutation (G1528C) in this population [14].
• Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene [15].

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

• Mitochondrial trifunctional protein (TP), an enzyme of beta-oxidation, is a multienzyme complex composed of four molecules of the alpha-subunit (HADHA) containing the enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase domains and four molecules of the beta-subunit (HADHB) containing the 3-ketoacyl-CoA thiolase domain [21].
• Although TP alpha S331A was insensitive to NO/PKG-desensitization, similar to wild type TP alpha its signaling was fully desensitized by the prostacyclin receptor agonist cicaprost occurring through a PKA-dependent mechanism [19].
• The pre-diagnostic test for preimplantation genetic diagnosis (PGD) of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency was performed by polymerase chain reaction (PCR) and direct sequencing for hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (HADHA) gene [22].
• We now report on a patient with LCHAD deficiency and hypoparathyroidism, evidenced by hypocalcemia, hyperphosphatemia, and a low level of parathyroid hormone, in whom the parathyroid glands could not be located after death [23].
• Liver and heart showed expression of both very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) mRNA [24].

Analytical, diagnostic and therapeutic context of HADHA

• To further elucidate pathogenesis of LCHAD retinopathy, we performed immunohistochemistry of the human eye and brain with antibodies to beta-oxidation enzymes [16].
• We obtained unexpected genotyping results of HADHA gene by allele drop-out in the analysis of patients' genomic DNA samples with a referred PCR primer set [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 [22].
• Deletion/site-directed mutagenesis and metabolic labeling studies identified Ser331 as the target residue of NO-induced PKG phosphorylation of TP alpha [19].
• Immunoblotting revealed expression of the MTP and enzyme assay showed the activity of LCHAD in the RPE cells [25].

References