Alternative titles; symbols
HGNC Approved Gene Symbol: ETHE1
SNOMEDCT: 723307008;
Cytogenetic location: 19q13.31 Genomic coordinates (GRCh38) : 19:43,506,719-43,527,201 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.31 | Ethylmalonic encephalopathy | 602473 | Autosomal recessive | 3 |
The ETHE1 gene encodes a mitochondrial sulfur dioxygenase involved in the catabolism of sulfide. It is a homodimer bound by a single iron atom and functions as a beta-lactamase-like iron-coordinating metalloprotein (summary by Tiranti et al., 2009).
Higashitsuji et al. (2002) identified the HSCO gene as a novel protein expressed in hepatoma that accelerates export of NFKB (see 164011) from the nucleus and inhibits p53 (191170)-dependent apoptosis. By homozygosity mapping and integrative genomics analysis, Tiranti et al. (2004) identified HSCO, also known as D83198 (GenBank D83198), as the gene in chromosome 19q13 responsible for ethylmalonic encephalopathy (602473) when mutated. They renamed the gene ETHE1 in light of its relationship to the disorder. The ETHE1 protein is a phylogenetically conserved protein that shares high homology with GLO2 (138760). Northern blot analysis showed ubiquitous expression of ETHE1 as a single transcript of approximately 1,000 nucleotides. The protein contains an N-terminal sequence of 24 amino acids whose residues show similarity to those of mitochondrial leader peptides. The ETHE1 protein is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of the leader peptide.
Tiranti et al. (2004) determined that the ETHE1 gene contains 7 exons.
The ETHE1 gene maps to chromosome 19q13 (Tiranti et al., 2004).
Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Tiranti et al. (2009) demonstrated that sulfur dioxygenase activity was markedly increased by ETHE1 overexpression in HeLa cells and E. coli. These findings indicated that ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide.
Kabil and Banerjee (2012) isolated the ETHE1 enzyme and determined its kinetic properties by studying the rate of oxygen consumption during conversion of glutathione persulfide (GSSH) to sulfite. Two mutant proteins, T152I and D196N, had lower iron content than the wildtype enzyme. Kinetic studies showed that the T152I enzyme had a 4-fold decrease in Vmax for the reaction compared to wildtype, whereas Km for GSSH was unaffected. D196N had a 15% decrease in Vmax and a 2-fold increase in Km for GSSH compared to wildtype. Both mutant proteins were less stable than wildtype. These studies did not provide a direct explanation for the biochemical features of patients with ETHE1 mutations, but did show that the ETHE1 reaction is oxygen-dependent and may be limited under hypoxic conditions.
By a combination of homozygosity mapping, integration of physical and functional genomic datasets, and mutational screening, Tiranti et al. (2004) identified the ETHE1 gene as well as mutations in this gene that cause ethylmalonic encephalopathy (EE; 602473), a devastating infantile metabolic disorder in which high levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle. The severe consequences of its malfunctioning indicated an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism. Tiranti et al. (2004) showed that the ETHE1 gene is located on 19q13 by linkage mapping. Because of the clinical and biochemical features of EE, they assumed that the responsible protein was likely to be involved in mitochondrial metabolism. After excluding 2 such known genes that map to 19q13, they selected candidate genes that predicted proteins of unknown function, which may potentially be involved in mitochondria. For this, they followed an integrated genomics approach that was originally developed (Mootha et al., 2003) to identify LRPPRC (607544) mutations, which are responsible for a form of cytochrome c oxidase deficiency (MC4DN5; 220111). According to this strategy, a 'neighborhood index' was given to all genes of the critical region; this index reflected the similarity of their RNA expression profiles to those of known mitochondrial genes. Through sequencing of the 7 exons of the ETHE1 gene, Tiranti et al. (2004) found homozygous mutations in all probands from the 4 consanguineous families originally used for gene mapping, as well as in a fifth family originally presumed to be nonconsanguineous. The proband in a sixth family was a compound heterozygote. Mutations were also found in 8 additional probands belonging to 4 consanguineous and 2 nonconsanguineous families, as well as in 4 unrelated singleton patients. Most of the 16 different mutations were loss-of-function mutations producing a stop, a frameshift, or aberrant splicing. In one consanguineous family, the entire gene was missing, and in 2 others, exon 4 was missing in both alleles. Tiranti et al. (2004) detected 6 missense mutations, all predicting amino acid changes at highly conserved positions.
Even though ethylmalonic encephalopathy has mainly been described in families from the Mediterranean basin and the Arabian peninsula, Tiranti et al. (2004) obtained no evidence for the existence of an ancestral haplotype or a cluster of common mutations in their cohort of patients with EE. Since the initial report, no more than 30 cases of EE had been described worldwide, leading to the assumption that EE is a very rare disorder. However, the actual incidence of this condition could have been significantly underestimated because the biochemical phenotype was incorrectly attributed to other metabolic disorders, particularly defects of the mitochondrial electron-transfer flavoprotein pathway.
In 14 patients with ethylmalonic encephalopathy, Mineri et al. (2008) identified homozygosity for mutations in the ETHE1 gene (see, e.g., 608451.0006 and 608451.0007). At the time of the report, 11 patients were deceased; age of death ranged from 18 months to 3 years. Three patients were alive at 6 months, 7 years, and 13 years.
In a pair of Yugoslavian identical twins with ethylmalonic encephalopathy, Pigeon et al. (2009) identified compound heterozygous mutations in the ETHE1 gene (L185R, 608451.0008 and Q27K, 608451.0009). Functional studies in patient cells were not performed.
Kitzler et al. (2019) identified homozygosity for the Q27K mutation in the ETHE1 gene in a 19-year-old man with EE. The mutation was identified by Sanger sequencing of the ETHE1 gene, and both parents were shown to be mutation carriers. Functional studies in patient cells were not performed.
In an Indian boy, born of consanguineous parents, with EE, Govindaraj et al. (2020) identified a homozygous mutation in the ETHE1 gene (D165H; 608451.0010). The mutation was identified by whole-exome sequencing. Respiratory chain activity testing in patient muscle demonstrated an isolated defect of complex IV activity. ETHE1 protein was reduced in patient muscle tissue, as were proteins associated with respiratory chain complexes I, II, and IV.
In a 4-year-old boy, born of consanguineous parents, with EE, Kashima et al. (2023) identified a homozygous mutation in the ETHE1 gene (D196N; 608451.0011). The mutation was identified by whole-exome sequencing. Functional studies in patient cells were not performed.
Platt et al. (2023) reviewed the biallelic mutations that had been identified in the ETHE1 gene in 45 patients with EE. Thirty-two patients had homozygous mutations, and 13 patients had compound heterozygous mutations. Thirty different mutations were identified, with the most common being R163Q, deletion of exon 4 (608451.0007), and R163W (608451.0001).
Tiranti et al. (2009) found that Ethe1-null mice developed the cardinal features of ethylmalonic encephalopathy, including poor growth, reduced motor activity, early death, low cytochrome c oxidase (COX) in muscle and brain, and increased urinary excretion of ethylmalonic acid. Both mutant mice and humans with the disorder excreted massive amounts of thiosulfate in the urine, and there was an accumulation of thiosulfate and hydrogen sulfide (H2S) in mutant mouse tissue. Hydrogen sulfide is powerful inhibitor of COX and short-chain fatty acid oxidation, and has vasoactive and vasotoxic effects. The findings suggested that ethylmalonic encephalopathy is a disease associated with impaired catabolism of inorganic sulfur leading to accumulation of hydrogen sulfide in key tissues. The toxic effects of this accumulation can account for several features, including ethylmalonic aciduria, COX deficiency, microangiopathy, acrocyanosis, and chronic diarrhea. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1-null mice, but it was markedly increased by ETHE1 overexpression in HeLa cells and E. coli. These findings indicated that ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.
In a patient with ethylmalonic encephalopathy (EE; 602473) from a consanguineous family, Tiranti et al. (2004) found a 487C-T transition in exon 4 of the ETHE1 gene, predicted to result in an arg163-to-trp amino acid change (R163W). The same missense mutation was found in 2 other unrelated probands. The haplotypes in these cases differed from each other, suggesting that the mutational event occurred either independently or in a very ancient common progenitor.
In a patient with ethylmalonic encephalopathy (EE; 602473) from a consanguineous family, Tiranti et al. (2004) found a change of the initiation codon from ATG (met) to ATT (ile).
In a patient with ethylmalonic encephalopathy (EE; 602473) from a consanguineous family, Tiranti et al. (2004) identified a 1-bp insertion, 604_605insG, in exon 6 of the ETHE1 gene, predicted to result in frameshift and premature termination (Val202fsTer220).
In a patient with ethylmalonic encephalopathy (EE; 602473) from a nonconsanguineous family, Tiranti et al. (2004) found compound heterozygosity for a 1-bp insertion (221_222insA) in exon 2 of the ETHE1 gene, resulting in a tyr74-to-ter (Y74X) change, and an 11-bp deletion (440del11; 608451.0005) in exon 4 of the ETHE1 gene, resulting in a frameshift and premature termination. The same 1-bp insertion was found in homozygous state in another patient.
For discussion of the 11-bp deletion (440del11) in the ETHE1 gene that was found in compound heterozygous state in a patient with ethylmalonic encephalopathy (EE; 602473) by Tiranti et al. (2004), see 608451.0004.
In 4 unrelated Arab patients with ethylmalonic encephalopathy (602473), Mineri et al. (2008) identified a homozygous G-to-T transversion (505+1G-T) in intron 4 of the ETHE1 gene, resulting in a frameshift and premature termination. Haplotype analysis suggested a founder effect. The mutation had previously been reported by Tiranti et al. (2004).
In 2 unrelated Arab patients with ethylmalonic encephalopathy (602473), Mineri et al. (2008) identified a homozygous deletion of exon 4 of the ETHE1 gene. Haplotype analysis suggested a founder effect. The mutation had previously been reported by Tiranti et al. (2004).
Drousiotou et al. (2011) identified a homozygous deletion of exon 4 of the ETHE1 gene in a patient of Greek Cypriot origin with ethylmalonic encephalopathy. Both parents were heterozygous for the deletion. An unrelated Greek Cypriot girl was compound heterozygous for the exon 4 deletion and a missense mutation (608451.0008). Haplotype analysis of both patients and 3 carrier parents showed that the exon 4 deletion occurred on the same haplotype as that found in Arab patients with the deletion. Western blot analysis showed complete absence of the ETHE1 protein.
In a girl of Greek Cypriot origin with ethylmalonic encephalopathy (EE; 602473), Drousiotou et al. (2011) identified compound heterozygosity for 2 mutations in the ETHE1 gene: a 554T-G transversion in exon 5, resulting in a leu185-to-arg (L185R) substitution, and a deletion of exon 4 (608451.0007). Her mother was heterozygous for the L185R mutation, and her father was heterozygous for the exon 4 deletion. No DNA from her deceased older brother was available for testing, but based on findings in the family was assumed to have the same genotype as his sister. Western blot analysis showed complete absence of the ETHE1 protein, consistent with the L185R mutant being unstable and degraded.
In a pair of Yugoslavian identical twins with EE, Pigeon et al. (2009) identified compound heterozygous mutations in the ETHE1 gene: L185R and a c.79C-A transversion resulting in a gln27-to-lys (Q27K; 608451.0009) substitution. The mutations were identified by sequencing of the ETHE1 gene. The parents and an unaffected sib were found to be mutation carriers.
For discussion of the c.79C-A transversion in the ETHE1 gene, resulting in a gln27-to-lys (Q27K) substitution, that was identified in compound heterozygous state in a pair of Yugoslavian identical twins with ethylmalonic encephalopathy (EE; 602473) by Pigeon et al. (2009), see 608451.0008.
In a 19-year-old man with EE, Kitzler et al. (2019) identified homozygosity for the Q27K mutation in the ETHE1 gene. The mutation, which was identified by Sanger sequencing of the ETHE1 gene, was present in heterozygous state in the parents.
In an Indian patient, born to consanguineous parents, with ethylmalonic encephalopathy (EE; 602473), Govindaraj et al. (2020) identified homozygosity for a c.493G-C transversion in the ETHE1 gene, resulting in an asp165-to-his (D165H) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was not present in the 1000 Genomes Project, ExAC, and gnomAD databases or in an internal database of 180 healthy patients. ETHE1 protein was reduced in patient muscle tissue.
In a 4-year-old boy, born to consanguineous parents, with ethylmalonic encephalopathy (EE; 602473), Kashima et al. (2023) identified homozygosity for a c.586G-A transition in the ETHE1 gene, resulting in an asp196-to-asn (D196N) substitution. The mutation was identified by whole-exome sequencing.
Drousiotou, A., DiMeo, I., Mineri, R., Georgiou, T., Stylianidou, G., Tiranti, V. Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches. Clin. Genet. 79: 385-390, 2011. [PubMed: 20528888] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01457.x]
Govindaraj, P., Parayil Sankaran, B., Nagappa, M., Arvinda, H. R., Deepha, S., Jessiena Ponmalar, J. N., Sinha, S., Gayathri, N., Taly, A. B. Child neurology: ethylmalonic encephalopathy. Neurology 94: e1336-e1339, 2020. [PubMed: 32111695] [Full Text: https://doi.org/10.1212/WNL.0000000000009144]
Higashitsuji, H., Higashitsuji, H., Nagao, T., Nonoguchi, K., Fujii, S., Itoh, K., Fujita, J. A novel protein overexpressed in hepatoma accelerates export of NF-kappa B from the nucleus and inhibits p53-dependent apoptosis. Cancer Cell 2: 335-346, 2002. [PubMed: 12398897] [Full Text: https://doi.org/10.1016/s1535-6108(02)00152-6]
Kabil, O., Banerjee, R. Characterization of patient mutations in human persulfide dioxygenase (ETHE1) involved in H2S catabolism. J. Biol. Chem. 287: 44561-44567, 2012. [PubMed: 23144459] [Full Text: https://doi.org/10.1074/jbc.M112.407411]
Kashima, D. T., Sloan-Heggen, C. M., Gottlieb-Smith, R. J., Barone Pritchard, A. An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant. Am. J. Med. Genet. 191A: 1614-1618, 2023. [PubMed: 36891747] [Full Text: https://doi.org/10.1002/ajmg.a.63176]
Kitzler, T. M., Gupta, I. R., Osterman, B., Poulin, C., Trakadis, Y., Waters, P. J., Buhas, D. C. Acute and chronic management in an atypical case of ethylmalonic encephalopathy. JIMD Rep. 45: 57-63, 2019. [PubMed: 30349987] [Full Text: https://doi.org/10.1007/8904_2018_136]
Mineri, R., Rimoldi, M., Burlina, A. B., Koskull, S., Perletti, C., Heese, B., von Dobeln, U., Mereghetti, P., Di Meo, I., Invernizzi, F., Zeviani, M., Uziel, G., Tiranti, V. Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. (Letter) J. Med. Genet. 45: 473-478, 2008. [PubMed: 18593870] [Full Text: https://doi.org/10.1136/jmg.2008.058271]
Mootha, V. K., Lepage, P., Miller, K., Bunkenborg, J., Reich, M., Hjerrild, M., Delmonte, T., Villeneuve, A., Sladek, R., Xu, F., Mitchell, G. A., Morin, C., Mann, M., Hudson, T. J., Robinson, B., Rioux, J. D., Lander, E. S. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc. Nat. Acad. Sci. 100: 605-610, 2003. [PubMed: 12529507] [Full Text: https://doi.org/10.1073/pnas.242716699]
Pigeon, N., Campeau, P. M., Cyr, D., Lemieux, B., Clarke, J. T. Clinical heterogeneity in ethylmalonic encephalopathy. J. Child Neurol 24: 991-996, 2009. [PubMed: 19289697] [Full Text: https://doi.org/10.1177/0883073808331359]
Platt, I., Bisgin, A., Kilavuz, S. Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype. Neurol. Sci. 44: 3827-3852, 2023. [PubMed: 37458841] [Full Text: https://doi.org/10.1007/s10072-023-06904-8]
Tiranti, V., D'Adamo, P., Briem, E., Ferrari, G., Mineri, R., Lamantea, E., Mandel, H., Balestri, P., Garcia-Silva, M.-T., Vollmer, B., Rinaldo, P., Hahn, S. H., 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. 74: 239-252, 2004. [PubMed: 14732903] [Full Text: https://doi.org/10.1086/381653]
Tiranti, V., Viscomi, C., Hildebrandt, T., Di Meo, I., Mineri, R., Tiveron, C., Levitt, M. D., Prelle, A., Fagiolari, G., Rimoldi, M., Zeviani, M. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nature Med. 15: 200-205, 2009. Note: Erratum: Nature Med. 15: 220 only, 2009. [PubMed: 19136963] [Full Text: https://doi.org/10.1038/nm.1907]