Alternative titles; symbols
HGNC Approved Gene Symbol: ECHS1
Cytogenetic location: 10q26.3 Genomic coordinates (GRCh38) : 10:133,362,485-133,373,354 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q26.3 | Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency | 616277 | Autosomal recessive | 3 |
The ECHS1 gene encodes short-chain enoyl-CoA hydratase (SCEH; EC 4.2.1.17), which catalyzes the second step in mitochondrial fatty acid beta-oxidation (summary by Kanazawa et al., 1993). The enzyme is also active in the isoleucine and valine catabolic pathways. In the valine catabolic pathway, ECHS1 acts upstream of HIBCH (610690) and converts methacrylyl-CoA to (S)-3-hydroxyisobutyryl-CoA and acryloyl-CoA to 3-hydroxypropionyl-CoA (summary by Peters et al., 2014).
By using rat SCEH cDNAs to probe a human liver library, Kanazawa et al. (1993) isolated human SCEH cDNAs. The predicted 290-amino acid human protein is 87% identical to that of the rat gene. By Northern blot analysis, Kanazawa et al. (1993) found a single 1.6-kb mRNA species transcribed most strongly in human liver, but also in fibroblast and muscle.
Janssen et al. (1997) isolated 2 overlapping genomic clones encompassing the entire human ECHS1 gene. They determined that the ECHS1 gene contains 8 exons and spans 11 kb of genomic DNA.
Janssen et al. (1997) mapped the ECHS1 gene to 10q26.2-q26.3 by fluorescence in situ hybridization.
By analysis of ECHS1 isolated from HEK293 cells, Yamada et al. (2015) showed that it had high substrate specificity for crotonyl-CoA and moderate specificity for acryloyl-CoA, 3-methylcrotonyl-CoA, and methacrylyl-CoA. ECHS1 bound to tiglyl-CoA, but hydrated only a small amount of this substrate.
Simon et al. (2021) identified a synonymous P163P variant in the ECHS1 gene (c.489G-A, 602292.0013) at an allele frequency of 0.17 in the Samoan population, with 34 homozygotes detected. This frequency did not suggest decreased fitness in individuals with homozygosity for the variant; however, Simon et al. (2021) found the variant to be disease causing in families with Samoan ancestry when in trans with a severe mutation on the other ECHS1 allele (e.g., A278T, 602202.0012).
In 2 infant sibs with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277) manifest as a severe fatal neurodegenerative disorder, Peters et al. (2014) identified compound heterozygous mutations in the ECHS1 gene (602292.0001 and 602292.0002). Patient fibroblasts showed significantly decreased ECHS1 activity and absence of the normal protein by immunoblot analysis. Peters et al. (2014) postulated that the enzymatic defect caused accumulation of the metabolites methacrylyl-CoA and acryloyl-CoA, which are toxic reactive intermediates that may have caused the brain pathology. Decreased activity of the pyruvate dehydrogenase complex (PDC) may also have been a secondary effect. The metabolic abnormalities in these patients appeared to be confined to the valine pathway.
In a boy with ECHS1D, Sakai et al. (2015) identified compound heterozygous mutations in the ECHS1 gene (602292.0003 and 602292.0004). The mutations, which were found by targeted exome sequencing, segregated with the disorder in the family. Patient cells also showed a combined mitochondrial respiratory chain deficiency, which was rescued by expression of wildtype ECHS1. These findings suggested a link between ECHS1 and the mitochondrial respiratory chain. Sakai et al. (2015) speculated that ECHS1 deficiency induced metabolic abnormalities resulting in the accumulation of toxic metabolites, such as glyoxylate, that secondarily inhibited normal mitochondrial respiratory function.
In 10 unrelated families segregating ECHS1D, Haack et al. (2015) identified homozygous or compound heterozygous mutations in the ECHS1 gene. In 1 family (F3), 3 affected sibs (proband 68552), born to consanguineous Pakistani parents, were homozygous for a missense mutation (Q159R; 602292.0007). In 2 unrelated families (F1 and F10), patient 346 and patient 52236 were compound heterozygous for the Q159R mutation and different second mutations (N59S, 602292.0005 and E77Q, 602292.0008), respectively. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the mutations in the family. Immunoblotting on fibroblasts from the 2 compound heterozygous patients showed reduced expression of the ECHS1 protein and reduced palmitate-dependent respiration; fibroblasts from 1 of these patients showed reduced 2-enoyl-CoA hydratase activity.
In 4 patients with ECHS1D from 3 unrelated French Canadian families, Tetreault et al. (2015) identified compound heterozygous mutations in the ECHS1 gene. Affected members in the 3 families had a T180A missense mutation (602292.0009) with a different second mutation (602292.0007, 602292.0010 and 602292.0011). All of the mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. All 4 mutations occurred in the ECHS1 enoyl-CoA hydratase/isomerase domain and were predicted to decrease protein stability.
In 3 Irish Traveler sibs and a Pakistani patient with ECHS1D, Fitzsimons et al. (2018) identified homozygosity for the previously identified Q159R and T180A mutations in the ECHS1 gene, respectively. Erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconic acid were elevated on urine organic acids of all patients. Muscle and fibroblast testing was carried out in 1 sib and the Pakistani patient. Fibroblasts showed markedly decreased ECHS1 enzyme activity and absence of ECHS1 on Western blot analysis. PDH activity and beta oxidation studies were normal. Activities of respiratory chain complexes I, II, and IV were normal, and activity of complexes II+III was decreased in muscle.
In 4 patients, including 3 sibs, from 2 families with ECHS1D, Simon et al. (2021) identified compound heterozygous mutations in the ECHS1 gene (A278T, 602292.0012 and P163P, 602292.0013). ECHS1 protein expression and activity were reduced in fibroblasts from the carrier parents from family 1 and reduced to a greater degree in their affected offspring. ECHS1 protein expression and activity were also reduced in fibroblasts from the patient in family 2. In both families, a Samoan parent was the carrier of the P163P variant. Analysis of mRNA from fibroblasts from the unaffected mother from family 1, who was homozygous for the P163P variant, and from one of her affected children demonstrated that the P163P variant resulted in abnormal splicing with skipping of exon 4. Family 1 was previously reported by Abdenur et al. (2020).
In 2 sibs with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), Peters et al. (2014) identified compound heterozygous mutations in the ECHS1 gene: a c.473C-A transversion in exon 4, resulting in an ala158-to-asp (A158D) substitution at a highly conserved residue at the entrance of the substrate-binding pocket of the enzyme; and a G-to-C transversion in intron 3 (c.414+3G-C; 602292.0002), resulting in a splicing defect and generation of a mutant protein lacking amino acids 126-138 at the interface between the 2 trimers of the hexameric structure.The mutations, which were found by direct sequencing of the ECHS1 gene based on biochemical abnormalities found in the patients, segregated with the disorder in the family and were not found in the dbSNP or Exome Variant Server databases. Patient fibroblasts showed significantly decreased ECHS1 activity and absence of the normal protein by immunoblot analysis.
For discussion of the c.414+3G-C mutation in the ECHS1 gene that was found in compound heterozygous state in patients with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277) by Peters et al. (2014), see 602292.0001.
In a patient with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), Sakai et al. (2015) identified compound heterozygous mutations in the ECHS1 gene: a c.2T-G transversion, resulting in a met1-to-arg (M1R) substitution in the initiation codon,and a c.5C-T transition, resulting in an ala2-to-val (A2V; 602292.0004) substitution. Both mutations occurred in the mitochondrial transit peptide. The mutations, which were found by targeted exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP (build 135) and 1000 Genomes Project databases, and segregated with the disorder in the family. Patient skeletal muscle cells showed severely decreased expression of ECHS1 and decreased activity (13%) of control values. Patient cells also showed a combined mitochondrial respiratory chain deficiency of complexes I, IV, and V, and these defects were rescued by expression of wildtype ECHS1. These findings suggested a link between ECHS1 and the mitochondrial respiratory chain. Sakai et al. (2015) speculated that ECHS1 deficiency induced metabolic abnormalities including accumulation of toxic metabolites, such as glyoxylate, that secondarily inhibited normal mitochondrial respiratory function.
For discussion of the ala2-to-val (A2V) mutation in the ECHS1 gene that was found in compound heterozygous state in a patient with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277) by Sakai et al. (2015), see 602292.0003.
In 2 sibs, born of unrelated Japanese parents, with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), Yamada et al. (2015) identified compound heterozygous mutations in the ECHS1 gene: a c.176A-G transition, resulting in an asn59-to-ser (N59S) substitution, and a c.413C-T transition, resulting in an ala138-to-val (A138V; 602292.0006) substitution. The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient fibroblasts showed severely decreased levels of ECHS1 protein with normal levels of mRNA, suggesting that the mutant protein is unstable. ECHS1 activity towards different substrates was decreased to between 2.6% and 6.2% of normal controls. In vitro functional expression studies showed that the D59S mutant was nonfunctional, whereas the A138V mutant had about 30% residual activity.
For discussion of the N59S mutation in the ECHS1 gene that was found in compound heterozygous state in a patient (patient 346, family 1) with ECHS1D by Haack et al. (2015), see 602292.0007.
For discussion of the c.413C-T transition in the ECHS1 gene, resulting in an ala138-to-val (A138V) substitution, that was found in compound heterozygous state in sibs with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277) by Yamada et al. (2015), see 602292.0005.
In 3 sibs (proband 68552) with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), who were born to consanguineous Pakistani parents (family 3), Haack et al. (2015) identified a homozygous c.476A-G transition (c.476A-G, NM_004092.3) in exon 4 of the ECHS1 gene, resulting in a gln159-to-arg (Q159R) substitution. The mutation was identified by whole-exome sequencing in 1 sib and confirmed by Sanger sequencing from blood spots in the 2 other sibs (identical female twins), who were deceased. The parents were heterozygous for the mutation. Haack et al. (2015) identified the Q159R mutation in compound heterozygosity with different ECHS1 mutations in 2 unrelated patients with ECHS1D: patient 346 (family 1) had the previously identified N9S mutation (602292.0005) and patient 52236 (family 10) had a c.229G-C transversion, resulting in a glu77-to-gln (E77Q; 602292.0009) substitution. Immunoblot analysis on fibroblasts from patients 346 and 52236 showed reduced expression of the ECHS1 protein; reduced palmitate-dependent respiration and reduced 2-enoyl-CoA hydratase activity was found in the fibroblasts of patient 52236. The Q159R variant had an allele frequency of 0.0001148 in the ExAC database, and the E77Q was not present in the database.
In 3 Irish Traveler sibs with ECHS1D, Fitzsimons et al. (2018) identified homozygosity for the Q159R mutation in the ECHS1 gene. Erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconic acid were elevated on urine organic acids of all patients. Muscle and fibroblast testing was carried out in 1 sib. Fibroblasts showed markedly decreased ECHS1 enzyme activity and absence of ECHS1 on Western blot analysis. PDH activity and beta oxidation studies were normal. Activities of respiratory chain complexes I, II, and IV were normal, and activity of complexes II+III was decreased in muscle.
For discussion of the Q159R mutation in the ESCHS1 gene that was found in compound heterozygosity in a patient (P4) with ESCHS1D by Tetreault et al. (2015), see 602292.0009.
For discussion of the c.229G-C transversion (c.229G-C, NM_004092.3) in the ECHS1 gene, resulting in a glu77-to-gln (E77Q) substitution, that was found in compound heterozygous state in a patient with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277) by Haack et al. (2015), see 602292.0007.
In 4 patients from 3 unrelated French Canadian families with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), Tetreault et al. (2015) identified compound heterozygous mutations in the ECHS1 gene. All patients had a c.538A-G transition (c.538A-G, NM_004092) in exon 5, resulting in a thr180-to-ala (T180A) substitution; in patient 1 (P1), the second mutation was a c.583G-A transition in exon 5, resulting in a gly195-to-ser (G195S; 602292.0010) substitution; in 2 sibs (P2 and P3), the second mutation was a c.713C-T transition in exon 6, resulting in an ala238-to-val (A238V; 602292.0011) substitution; and in P4, the second mutation was Q159R (602292.0007). The mutations segregated with the disorder in the families. All of the mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. None of these variants were present in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 138) databases, except for Q159R, which was reported once in EVS. All 4 mutations were in the ECHS1 enoyl-CoA hydratase/isomerase domain and were predicted to decrease protein stability. Tetreault et al. (2015) found that the patients with the T180A variant shared a common haplotype, suggesting that the variant derives from a single ancestral mutation. The haplotype was not observed in 10 unrelated French Canadian control samples.
In a Pakistani patient with ECHS1D, Fitzsimons et al. (2018) identified homozygosity for the T180A mutation. Erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconic acid were elevated on urine organic acids. Patient fibroblasts showed markedly decreased ECHS1 enzyme activity and absence of ECHS1 on Western blot analysis. PDH activity and beta oxidation studies were normal. Activities of respiratory chain complexes I, II, and IV were normal, and activity of complexes II+III was decreased in muscle.
For discussion of the c.583G-A transition (c.583G-C, NM_004092) in exon 5 of the ECHS1 gene, resulting in a gly195-to-ser (G195S) substitution, that was found in a patient (P1) with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277) by Tetreault et al. (2015), see 602292.0009.
For discussion of the c.713C-T transition (c.713C-T, NM_004092) in exon 6 of the ECHS1 gene, resulting in an ala238-to-val (A238V) substitution, that was found in 2 sibs (P2 and P3) with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277) by Tetreault et al. (2015), see 602292.0009.
In 4 patients, including 3 sibs, from 2 families with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), Simon et al. (2021) identified compound heterozygous mutations in the ECHS1 gene: a c.832G-A transition (c.832G-A, NM_004092), resulting in an ala278-to-thr (A278T) substitution, and a c.489G-A transition (602292.0013), resulting in a pro163-to-pro (P163P) synonymous change leading to a splicing abnormality. The mutations were identified by whole-exome sequencing, whole-genome sequencing, and Sanger sequencing of cDNA, and segregated with disease in both families. In both families, the P163P variant was inherited from a Samoan parent. The A278T variant was present in the gnomAD database (v2.1.1) at an allele frequency of 6.5x10(-5) in the South Asian population and 7.7x10(-7) in the European non-Finnish population, and the P163P mutation was present at an allele frequency of 0.001 in the overall population and 0.01 in the East Asian population with 2 homozygotes reported. ECHS1 protein expression and enzyme activity were reduced in fibroblasts from the unaffected carrier parents from family 1 and reduced to a greater degree in their affected offspring. ECHS1 protein expression and activity were also reduced in fibroblasts from the patient in family 2.
For discussion of the c.489G-A transition (c.489G-A, NM_004092) in the ECHS1 gene, resulting in a pro163-to-pro (P163P) synonymous change leading to a splicing abnormality, that was identified in compound heterozygous state in 4 patients, including 3 sibs, from 2 families with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277) by Simon et al. (2021), see 602292.0012.
Abdenur, J. E., Sowa, M., Simon, M., Steenari, M., Skaar, J., Eftekharian, S., Chang, R., Ferdinandusse, S., Pitt, J. Medical nutrition therapy in patients with HIBCH and ECHS1 defects: clinical and biochemical response to low valine diet. Molec. Genet. Metab. Rep. 24: 100617, 2020. [PubMed: 32642440] [Full Text: https://doi.org/10.1016/j.ymgmr.2020.100617]
Fitzsimons, P. E., Alston, C. L., Bonnen, P. E., Hughes, J., Crushell, E., Geraghty, M. T., Tetreault, M., O'Reilly, P., Twomey, E., Sheikh, Y., Walsh, R., Waterham, H. R., Ferdinandusse, S., Wanders, R. J. A., Taylor, R. W., Pitt, J. J., Mayne, P. D. Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency. Am. J. Med. Genet. 176A: 1115-1127, 2018. [PubMed: 29575569] [Full Text: https://doi.org/10.1002/ajmg.a.38658]
Haack, T. B., Jackson, C. B., Murayama, K., Kremer, L. S., Schaller, A., Kotzaeridou, U., de Vries, M. C., Schottmann, G., Santra, S., Buchner, B., Wieland, T., Graf, E., and 28 others. Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann. Clin. Transl. Neurol. 2: 492-509, 2015. [PubMed: 26000322] [Full Text: https://doi.org/10.1002/acn3.189]
Janssen, U., Davis, E. M., Le Beau, M. M., Stoffel, W. Human mitochondrial enoyl-CoA hydratase gene (ECHS1): structural organization and assignment to chromosome 10q26.2-q26.3. Genomics 40: 470-475, 1997. [PubMed: 9073515] [Full Text: https://doi.org/10.1006/geno.1996.4597]
Kanazawa, M., Ohtake, A., Abe, H., Yamamoto, S., Satoh, Y., Takayanagi, M., Niimi, H., Mori, M., Hashimoto, T. Molecular cloning and sequence analysis of the cDNA for human mitochondrial short-chain enoyl-CoA hydratase. Enzyme Protein 47: 9-13, 1993. [PubMed: 8012501] [Full Text: https://doi.org/10.1159/000468650]
Peters, H., Buck, N., Wanders, R., Ruiter, J., Waterham, H., Koster, J., Yaplito-Lee, J., Ferdinandusse, S., Pitt, J. ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain 137: 2903-2908, 2014. [PubMed: 25125611] [Full Text: https://doi.org/10.1093/brain/awu216]
Sakai, C., Yamaguchi, S., Sasaki, M., Miyamoto, Y., Matsushima, Y., Goto, Y. ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum. Mutat. 36: 232-239, 2015. [PubMed: 25393721] [Full Text: https://doi.org/10.1002/humu.22730]
Simon, M. T., Eftekharian, S. S., Ferdinandusse, S., Tang, S., Naseri, T., Reupena, M. S., McGarvey, S. T., Minster, R. L., Weeks, D. E., Samoan Obesity, Lifestyle, and Genetic Adaptations (OLaGA) Study Group, Nguyen, D. D., Lee, S., Ellsworth, K. A., Vaz, F. M., Dimmock, D., Pitt, J., Abdenur, J. E. ECHS1 disease in two unrelated families of Samoan descent: common variant--rare disorder. Am. J. Med. Genet. 185A: 157-167, 2021. [PubMed: 33112498] [Full Text: https://doi.org/10.1002/ajmg.a.61936]
Tetreault, M., Fahiminiya, S., Antonicka, H., Mitchell, G. A., Geraghty, M. T., Lines, M., Boycott, K. M., Shoubridge, E. A., Mitchell, J. J., Care4Rare Canada Consortium, Michaud, J. L., Majewski, J. Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. Hum. Genet. 134: 981-991, 2015. [PubMed: 26099313] [Full Text: https://doi.org/10.1007/s00439-015-1577-y]
Yamada, K., Aiba, K., Kitaura, Y., Kondo, Y., Nomura, N., Nakamura, Y., Fukushi, D., Murayama, K., Shimomura, Y., Pitt, J., Yamaguchi, S., Yokochi, K., Wakamatsu, N. Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion. J. Med. Genet. 52: 691-698, 2015. [PubMed: 26251176] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103231]