Ethylmalonic Encephalopathy Is Caused by Mutations in ETHE1, a Gene Encoding a Mitochondrial Matrix Protein

Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute Carlo Besta, Milan, Italy.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2004; 74(2):239-52. DOI: 10.1086/381653
Source: PubMed


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.

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Available from: Adamo Pio d'Adamo, Oct 03, 2015
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    • "Whilst the R163 residue is evolutionarily conserved and the pathogenic role of the Q163 variant has been experimentally demonstrated (Henriques et al. 2014), the I114 residue is poorly conserved, making it possible for the I114F change to be a rare non pathogenic variant (multiple alignments of the ETHE1 protein sequences in different species are showed in Fig. 4). By using a constitutive Ethe1−/− mouse model, Tiranti et al. (2004) showed that the main consequence of ETHE1 loss is the accumulation of hydrogen sulfide (H 2 S), a product of intestinal anaerobes and, in trace amount, tissues. Increased concentration of sulfide in tissues (i.e. "
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    ABSTRACT: Ethylmalonic encephalopathy (EE) is a rare autosomal recessive disorder characterized by early onset encephalopathy, chronic diarrhoea, petechiae, orthostatic acrocyanosis and defective cytochrome c oxidase (COX) in muscle and brain. High levels of lactic, ethylmalonic and methylsuccinic acids are detected in body fluids. EE is caused by mutations in ETHE1 gene, a mitochondrial sulfur dioxygenase. Neurologic signs and symptoms include progressively delayed development, hypotonia, seizures, and abnormal movements. We report on the clinical, electroencephalographic and MRI findings of a baby with a severe early onset encephalopathy associated with novel ETHE1 gene mutation. This is the first case described in literature with an early pure epileptic onset, presenting with West syndrome.
    Metabolic Brain Disease 07/2015; DOI:10.1007/s11011-015-9707-8 · 2.64 Impact Factor
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    • "However, in a few cases, ETHE1 has been detected in patient cells which display a clinical phenotype indistinguishable from that of ETHE1 protein-negative cases, suggesting that in such circumstances the mutant protein lacks activity. Two such cases are those of the disease-associated ETHE1 mutations, found in homozygous EE patients, that both affect arginine-163, replacing it by tryptophan or glutamine [1], [9], [11]. Patient fibroblasts were protein positive but since these individuals were affected by EE, arginine 163 has been suggested to be critical for ETHE1 catalytic activity. "
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    ABSTRACT: ETHE1 is an iron-containing protein from the metallo β-lactamase family involved in the mitochondrial sulfide oxidation pathway. Mutations in ETHE1 causing loss of function result in sulfide toxicity and in the rare fatal disease Ethylmalonic Encephalopathy (EE). Frequently mutations resulting in depletion of ETHE1 in patient cells are due to severe structural and folding defects. However, some ETHE1 mutations yield nearly normal protein levels and in these cases disease mechanism was suspected to lie in compromised catalytic activity. To address this issue and to elicit how ETHE1 dysfunction results in EE, we have investigated two such pathological mutations, ETHE1-p.Arg163Gln and p.Arg163Trp. In addition, we report a number of benchmark properties of wild type human ETHE1, including for the first time the redox properties of the mononuclear iron centre. We show that loss of function in these variants results from a combination of decreased protein stability and activity. Although structural assessment revealed that the protein fold is not perturbed by mutations, both variants have decreased thermal stabilities and higher proteolytic susceptibilities. ETHE1 wild type and variants bind 1±0.2 mol iron/protein and no zinc; however, the variants exhibited only ≈10% of wild-type catalytically activity. Analysis of the redox properties of ETHE1 mononuclear iron centre revealed that the variants have lowered reduction potentials with respect to that of the wild type. This illustrates how point mutation-induced loss of function may arise via very discrete subtle conformational effects on the protein fold and active site chemistry, without extensive disruption of the protein structure or protein-cofactor association.
    PLoS ONE 09/2014; 9(9):e107157. DOI:10.1371/journal.pone.0107157 · 3.23 Impact Factor
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    • "SDO plays an essential role in both by oxidizing sulfane sulfur of glutathione persulfide (GSS−) to sulfite by using O2. SDO in humans was initially recognized as ETHE1 protein (ethylmalonic encephalopathy 1) since it was recognized that ETHE1 gene mutation leads to ethylmalonic encephalopathy (EE) [12]. Recently, Tiranti et al. [13] suggested that ETHE1 possesses SDO activity and is involved in the oxidation of sulfide since SDO activity 1) is absent in EE patients and ETHE1−/− mice, and 2) increases when human ETHE1 is overexpressed in Hela or E. coli cells. "
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    ABSTRACT: Sulfide is a common toxin to animals and is abundant in coastal and aquatic sediments. Sulfur dioxygenase (SDO) is thought to be the key enzyme involved in sulfide oxidation in some organisms. The echiuran worm, Urechis unicinctus, inhabits coastal sediment and tolerates high concentrations of sulfide. The SDO is presumably important for sulfide tolerance in U. unicinctus. The full-length cDNA of SDO from the echiuran worm U. unicinctus, proven to be located in the mitochondria, was cloned and the analysis of its sequence suggests that it belongs to the metallo-β-lactamase superfamily. The enzyme was produced using an E. coli expression system and the measured activity is approximately 0.80 U mg protein(-1). Furthermore, the expression of four sub-segments of the U. unicinctus SDO was accomplished leading to preliminary identification of functional domains of the enzyme. The identification of the conserved metal I (H113, H115, H169 and D188), metal II (D117, H118, H169 and H229) as well as the potential glutathione (GSH) (R197, Y231, M279 and I283) binding sites was determined by enzyme activity and GSH affinity measurements. The key residues responsible for SDO activity were identified by analysis of simultaneous mutations of residues D117 and H118 located close to the metal II binding site. The recombinant SDO from U. unicinctus was produced, purified and characterized. The metal binding sites in the SDO were identified and Y231 recognized as the mostly important amino acid residue for GSH binding. Our results show that SDO is located in the mitochondria where it plays an important role in sulfide detoxification of U. unicinctus.
    PLoS ONE 12/2013; 8(12):e81885. DOI:10.1371/journal.pone.0081885 · 3.23 Impact Factor
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