The HADHB gene provides instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. Mitochondrial trifunctional protein is made of eight parts (subunits). Four alpha subunits are produced from the HADHA gene, and four beta subunits are produced from the HADHB gene. As the name suggests, mitochondrial trifunctional protein contains three enzymes that each perform a different function. The beta subunits contain one of the enzymes, known as long-chain 3-keto-acyl-CoA thiolase. The alpha subunits contain the other two enzymes. These enzymes are essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them to energy.
Mitochondrial trifunctional protein is required to metabolize a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils. These fatty acids are stored in the body's fat tissues. Fatty acids are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.
Health Conditions Related to Genetic Changes
Mitochondrial trifunctional protein deficiency
Researchers have identified at least 26 mutations in the HADHB gene that cause mitochondrial trifunctional protein deficiency. These mutations reduce all three enzyme activities of mitochondrial trifunctional protein. Most mutations change one of the protein building blocks (amino acids) used to make the beta subunit. A change in amino acids probably alters the subunit's structure, which disrupts all three activities of the enzyme complex. Some mutations produce abnormally short, nonfunctional beta subunits and lead to decreased levels of mitochondrial trifunctional protein.
With a loss of mitochondrial trifunctional protein activity, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to some features of this disorder, such as a lack of energy (lethargy) and low blood sugar (hypoglycemia). Long-chain fatty acids or partially metabolized fatty acids may also build up and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of mitochondrial trifunctional protein deficiency.More About This Health Condition
A few mutations in the HADHB gene have been found to decrease only the long-chain 3-keto-acyl-CoA thiolase enzyme activity of mitochondrial trifunctional protein. These mutations change single amino acids used to make the beta subunit. The signs and symptoms of isolated long-chain 3-keto-acyl-CoA thiolase deficiency are similar to those of mitochondrial trifunctional protein deficiency. These features include feeding difficulties, lethargy, hypoglycemia, weak muscle tone (hypotonia), and liver problems. Infants with this disorder are also at high risk for serious heart problems, breathing difficulties, coma, and sudden death.
HADHB mutations appear to increase a woman's risk of developing two serious liver disorders during pregnancy, known as acute fatty liver of pregnancy (AFLP) and HELLP syndrome. AFLP begins with abdominal pain and can rapidly progress to liver failure. HELLP stands for hemolysis (the breakdown of red blood cells), elevated liver enzyme levels, and low platelets (cells involved with blood clotting). A small percentage of women who have a mutation in one copy of the HADHB gene and carry a fetus with mutations in both copies of the HADHB gene develop one of these maternal liver diseases. Little is known about the relationship between HADHB mutations and liver problems in the mother during pregnancy. One possibility is that partially metabolized long-chain fatty acids produced by the fetus or placenta accumulate in the mother and are toxic to the liver.
Other Names for This Gene
- hydroxyacyl dehydrogenase, subunit B
- hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), beta subunit
- hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), beta subunit
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Angdisen J, Moore VD, Cline JM, Payne RM, Ibdah JA. Mitochondrial trifunctional protein defects: molecular basis and novel therapeutic approaches. Curr Drug Targets Immune Endocr Metabol Disord. 2005 Mar;5(1):27-40. doi: 10.2174/1568008053174796. Citation on PubMed
- Choi JH, Yoon HR, Kim GH, Park SJ, Shin YL, Yoo HW. Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency. Int J Mol Med. 2007 Jan;19(1):81-7. Citation on PubMed
- Das AM, Illsinger S, Lucke T, Hartmann H, Ruiter JP, Steuerwald U, Waterham HR, Duran M, Wanders RJ. Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene. Clin Chem. 2006 Mar;52(3):530-4. doi: 10.1373/clinchem.2005.062000. Epub 2006 Jan 19. Citation on PubMed
- Eaton S, Bursby T, Middleton B, Pourfarzam M, Mills K, Johnson AW, Bartlett K. The mitochondrial trifunctional protein: centre of a beta-oxidation metabolon? Biochem Soc Trans. 2000 Feb;28(2):177-82. doi: 10.1042/bst0280177. Citation on PubMed
- Oey NA, den Boer ME, Wijburg FA, Vekemans M, Auge J, Steiner C, Wanders RJ, Waterham HR, Ruiter JP, Attie-Bitach T. Long-chain fatty acid oxidation during early human development. Pediatr Res. 2005 Jun;57(6):755-9. doi: 10.1203/01.PDR.0000161413.42874.74. Epub 2005 Apr 21. Citation on PubMed
- Orii KE, Aoyama T, Wakui K, Fukushima Y, Miyajima H, Yamaguchi S, Orii T, Kondo N, Hashimoto T. Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency. Hum Mol Genet. 1997 Aug;6(8):1215-24. doi: 10.1093/hmg/6.8.1215. Citation on PubMed
- Prasun P, LoPiccolo MK, Ginevic I. Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency. 2022 Sep 1. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK583531/ Citation on PubMed
- Sander J, Sander S, Steuerwald U, Janzen N, Peter M, Wanders RJ, Marquardt I, Korenke GC, Das AM. Neonatal screening for defects of the mitochondrial trifunctional protein. Mol Genet Metab. 2005 Jun;85(2):108-14. doi: 10.1016/j.ymgme.2005.02.002. Epub 2005 Mar 24. Citation on PubMed
- Shekhawat PS, Matern D, Strauss AW. Fetal fatty acid oxidation disorders, their effect on maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis and management. Pediatr Res. 2005 May;57(5 Pt 2):78R-86R. doi: 10.1203/01.PDR.0000159631.63843.3E. Epub 2005 Apr 6. Citation on PubMed or Free article on PubMed Central
- Spiekerkoetter U, Khuchua Z, Yue Z, Bennett MJ, Strauss AW. General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatr Res. 2004 Feb;55(2):190-6. doi: 10.1203/01.PDR.0000103931.80055.06. Epub 2003 Nov 19. Citation on PubMed
- Spiekerkoetter U, Lindner M, Santer R, Grotzke M, Baumgartner MR, Boehles H, Das A, Haase C, Hennermann JB, Karall D, de Klerk H, Knerr I, Koch HG, Plecko B, Roschinger W, Schwab KO, Scheible D, Wijburg FA, Zschocke J, Mayatepek E, Wendel U. Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis. 2009 Aug;32(4):488-97. doi: 10.1007/s10545-009-1125-9. Epub 2009 Apr 29. Citation on PubMed
- Spiekerkoetter U, Sun B, Khuchua Z, Bennett MJ, Strauss AW. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations. Hum Mutat. 2003 Jun;21(6):598-607. doi: 10.1002/humu.10211. Citation on PubMed
- Spierkerkoetter U, Khuchua Z, Yue Z, Strauss AW. The early-onset phenotype of mitochondrial trifunctional protein deficiency: a lethal disorder with multiple tissue involvement. J Inherit Metab Dis. 2004;27(2):294-6. doi: 10.1023/b:boli.0000028839.57386.88. Citation on PubMed
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