The ETHE1 gene provides instructions for making an enzyme that is active in mitochondria, which are the energy-producing centers in cells. The ETHE1 enzyme is part of a pathway that breaks down a molecule called sulfide (H2S) in mitochondria. Sulfide is produced in the body's tissues as part of normal cell processes, and it is also released by bacteria living in the gastrointestinal system (gut).
At low levels, sulfide is critical for normal cell functioning. However, this molecule becomes toxic at high levels, interfering with numerous cell activities. For example, excess sulfide interferes with mitochondrial energy production by blocking (inhibiting) an enzyme complex called cytochrome C oxidase (COX). This complex normally carries out one of the final steps in the process of energy production in mitochondria.
Health Conditions Related to Genetic Changes
More than 30 mutations in the ETHE1 gene have been identified in people with ethylmalonic encephalopathy. This rare condition affects many parts of the body, including the nervous system, blood vessels, and intestines. Signs and symptoms include delayed development, abnormal movements, rashes of tiny red spots under the skin (petechiae), blue discoloration of the hands and feet (acrocyanosis), and chronic diarrhea.
Most of the mutations that cause ethylmalonic encephalopathy lead to the production of nonfunctional versions of the ETHE1 enzyme or prevent cells from making any of this enzyme. A shortage of functional enzyme prevents sulfide from being broken down normally, allowing this molecule to accumulate in cells. The buildup of sulfide inhibits the activity of COX, which disrupts mitochondrial energy production and damages tissues and organs throughout the body. Researchers believe that the effects of excess sulfide in the brain, muscles, blood vessels, and lining of the intestines underlie most of the major features of ethylmalonic encephalopathy.More About This Health Condition
MedlinePlus Genetics provides information about Leigh syndromeMore About This Health Condition
Other Names for This Gene
- ethylmalonic encephalopathy 1
- Ethylmalonic encephalopathy protein 1
- hepatoma subtracted clone one
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Di Meo I, Fagiolari G, Prelle A, Viscomi C, Zeviani M, Tiranti V. Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy. Antioxid Redox Signal. 2011 Jul 15;15(2):353-62. doi: 10.1089/ars.2010.3520. Epub 2011 Feb 25. Citation on PubMed
- Pettinati I, Brem J, McDonough MA, Schofield CJ. Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy. Hum Mol Genet. 2015 May 1;24(9):2458-69. doi: 10.1093/hmg/ddv007. Epub 2015 Jan 16. Citation on PubMed or Free article on PubMed Central
- Tiranti V, Briem E, Lamantea E, Mineri R, Papaleo E, De Gioia L, Forlani F, Rinaldo P, Dickson P, Abu-Libdeh B, Cindro-Heberle L, Owaidha M, Jack RM, Christensen E, Burlina A, Zeviani M. ETHE1 mutations are specific to ethylmalonic encephalopathy. J Med Genet. 2006 Apr;43(4):340-6. doi: 10.1136/jmg.2005.036210. Epub 2005 Sep 23. Citation on PubMed or Free article on PubMed Central
- Tiranti V, D'Adamo P, Briem E, Ferrari G, Mineri R, Lamantea E, Mandel H, Balestri P, Garcia-Silva MT, Vollmer B, Rinaldo P, Hahn SH, Leonard J, Rahman S, Dionisi-Vici C, Garavaglia B, Gasparini P, Zeviani M. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am J Hum Genet. 2004 Feb;74(2):239-52. doi: 10.1086/381653. Epub 2004 Jan 19. Citation on PubMed or Free article on PubMed Central
- Tiranti V, Viscomi C, Hildebrandt T, Di Meo I, Mineri R, Tiveron C, Levitt MD, Prelle A, Fagiolari G, Rimoldi M, Zeviani M. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med. 2009 Feb;15(2):200-5. doi: 10.1038/nm.1907. Epub 2009 Jan 11. Erratum In: Nat Med. 2009 Feb;15(2):220. Citation on PubMed
- Tiranti V, Zeviani M. Altered sulfide (H(2)S) metabolism in ethylmalonic encephalopathy. Cold Spring Harb Perspect Biol. 2013 Jan 1;5(1):a011437. doi: 10.1101/cshperspect.a011437. Citation on PubMed or Free article on PubMed Central