Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.

Ethylmalonic encephalopathy (EE) is a devastating infantile metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels. High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle. By use of a combination of homozygosity mapping, integration of physical and functional genomic data sets, and mutational screening, we identified GenBank D83198 as the gene responsible for EE. We also demonstrated that the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The gene had previously been known as "HSCO" (for hepatoma subtracted clone one). However, given its role in EE, the name of the gene has been changed to "ETHE1." The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism.

[1]  M. Freeman,et al.  Mitochondrial membrane remodelling regulated by a conserved rhomboid protease , 2003, Nature.

[2]  Paul J Thornalley.  The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life. , 1990, The Biochemical journal.

[3]  E. Bertini,et al.  A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. , 1994, The Journal of pediatrics.

[4]  V. Talesa,et al.  Isolation of glyoxalase II from bovine liver mitochondria. , 1990, Biochemistry international.

[5]  E. Bertini,et al.  New clinical phenotype of branched-chain acyl-CoA oxidation defect , 1991, The Lancet.

[6]  P. Briza,et al.  Heterologous expression, purification, and kinetic comparison of the cytoplasmic and mitochondrial glyoxalase II enzymes, Glo2p and Glo4p, from Saccharomyces cerevisiae. , 1999, Protein expression and purification.

[7]  J. Ott,et al.  Strategies for multilocus linkage analysis in humans. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[8]  A. Ribes,et al.  Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria. , 1997, Pediatric neurology.

[9]  P. Srere,et al.  [1] Citrate synthase. [EC 4.1.3.7. Citrate oxaloacetate-lyase (CoA-acetylating)] , 1969 .

[10]  M. Koivusalo,et al.  Isolation of glyoxalase II from two different compartments of rat liver mitochondria. Kinetic and immunochemical characterization of the enzymes. , 1989, Biochimica et biophysica acta.

[11]  J. Fujita,et al.  A novel protein overexpressed in hepatoma accelerates export of NF-kappa B from the nucleus and inhibits p53-dependent apoptosis. , 2002, Cancer cell.

[12]  Eric S. Lander,et al.  Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  A. Kornberg.  [67] Lactic dehydrogenase of muscle: Pyruvate + DPNH ⇄ Lactate + DPN , 1955 .

[14]  H. Ramsdell,et al.  Identification of ethylmalonic acid in urine of two patients with the vomitting sickness of Jamaica. , 1976, Clinica chimica acta; international journal of clinical chemistry.

[15]  The active-site residue tyr-175 in human glyoxalase II contributes to binding of glutathione derivatives. , 2000, Biochimica et biophysica acta.

[16]  M. Breitenbach,et al.  Identification and Phenotypic Analysis of Two Glyoxalase II Encoding Genes from Saccharomyces cerevisiae,GLO2 and GLO4, and Intracellular Localization of the Corresponding Proteins* , 1997, The Journal of Biological Chemistry.

[17]  G. Gascon,et al.  Ethylmalonic aciduria: an organic acidemia with CNS involvement and vasculopathy , 1994, Brain & development (Tokyo. 1979).

[18]  L. Aravind,et al.  An evolutionary classification of the metallo-beta-lactamase fold proteins , 1998, Silico Biol..

[19]  U. Hellman,et al.  Molecular Cloning, Heterologous Expression, and Characterization of Human Glyoxalase II (*) , 1996, The Journal of Biological Chemistry.

[20]  G. Uziel,et al.  Muscle cytochromec oxidase deficiency in two Italian patients with ethylmalonic aciduria and peculiar clinical phenotype , 1994, Journal of Inherited Metabolic Disease.

[21]  G. Schatz,et al.  The biogenesis of mitochondria. , 1970, The Biochemical journal.

[22]  V. Tiranti,et al.  Characterization of SURF-1 expression and Surf-1p function in normal and disease conditions. , 1999, Human molecular genetics.

[23]  M. Genel,et al.  Ethylmalonic-adipic aciduria. In vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases. , 1979, The Journal of clinical investigation.

[24]  M. Rocchi,et al.  Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the Expressed Sequence Tags database. , 1997, Human molecular genetics.

[25]  Rosemary M. L. Tan,et al.  Ethylmalonic and methylsuccinic aciduria in ethylmalonic encephalopathy arise from abnormal isoleucine metabolism. , 1998, Metabolism: clinical and experimental.

[26]  O. Mamer,et al.  Demonstration of a new mammalian isoleucine catabolic pathway yielding an Rseries of metabolites. , 1976, The Biochemical journal.

[27]  G. Morgese,et al.  Ethylmalonic encephalopathy , 2002, Journal of Neurology.

[28]  K Lange,et al.  Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. , 1996, American journal of human genetics.

[29]  P. Fernández-Silva,et al.  The human mitochondrial transcription termination factor (mTERF) is a multizipper protein but binds to DNA as a monomer, with evidence pointing to intramolecular leucine zipper interactions , 1997, The EMBO journal.

[30]  J. Vockley,et al.  Role of Common Gene Variations in the Molecular Pathogenesis of Short-Chain Acyl-CoA Dehydrogenase Deficiency , 2001, Pediatric Research.