Alternative titles; symbols
HGNC Approved Gene Symbol: MECR
SNOMEDCT: 1236805005;
Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38) : 1:29,167,696-29,230,934 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p35.3 | Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities | 617282 | Autosomal recessive | 3 |
| Optic atrophy 16 | 620629 | Autosomal recessive | 3 |
The MECR gene encodes the last step of mitochondrial fatty acid synthesis. It is involved in the synthesis of lipoic acid and is required for mitochondrial respiratory competence (summary by Heimer et al., 2016).
By searching an EST database for sequences similar to S. cerevisiae trans-2-enoyl thioesterase, followed by PCR amplification, Miinalainen et al. (2003) cloned NRBF1. The deduced 373-amino acid protein has a calculated molecular mass of 37 kD. Homologous proteins were identified in mammalian, nematode, and yeast databases. The mammalian proteins contain a putative N-terminal mitochondrial targeting signal, and all contain a tyrosine residue critical for catalysis in the yeast enzyme. Northern blot analysis detected a 1.4-kb NRBF1 transcript expressed at highest levels in skeletal and heart muscle. Expression was weaker in brain, placenta, liver, kidney, and pancreas, and no expression was detected in lung. SDS-PAGE showed that purified recombinant NRBF1 had an apparent molecular mass of about 37 kD. Size exclusion chromatography estimated a native mass of 65 kD, indicating that NRBF1 forms homodimers.
Miinalainen et al. (2003) demonstrated that recombinant NRBF1 reduced trans-2-enoyl-CoA to acyl-CoA with chain lengths from C6 to C16 in an NADPH-dependent manner, with preference for medium chain-length substrates. Furthermore, expression of human NRBF1 in a yeast strain deficient in 2-enoyl thioester reductase restored mitochondrial respiratory function and allowed growth on glycerol.
Miinalainen et al. (2003) determined that the NRBF1 gene contains 10 exons and spans more than 37 kb.
By genomic sequence analysis, Miinalainen et al. (2003) mapped the NRBF1 gene to chromosome 1p22.3.
Dystonia, Childhood-Onset, with Optic Atrophy and Basal Ganglia Abnormalities
In 7 patients from 5 unrelated families with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG; 617282), Heimer et al. (2016) identified biallelic mutations in the MECR gene (608205.0001-608205.0006). The mutations, which were found by either whole-exome sequencing or direct sequencing of the MECR gene, were confirmed by Sanger sequencing and segregated with the disorder in the families. Patient fibroblasts from 4 families showed strongly reduced levels of MECR protein and about a 50% decrease in protein lipoylation compared to controls. Some patient cells also showed mild and variable decreases in mitochondrial respiratory chain and electron transport system activities. Patient cells did not show changes in mitochondrial morphology compared to controls. Two of the variants failed to fully rescue a growth defect in yeast complementation assays, consistent with a loss-of-function effect.
In a 12-year-old boy with childhood-onset dystonia and basal ganglia abnormalities but without optic atrophy, who was born to consanguineous Chinese parents (family G), Liu et al. (2021) identified a homozygous mutation in the MECR gene (D304Y; 608205.0007). The authors noted that the patient was treated with lipoic acid since age 10, which may explain the absence of optic atrophy. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents and an unaffected sib. MECR protein expression was reduced in patient fibroblasts. Molecular modeling suggested that the D304Y mutation resulted in disturbed protein stability.
Optic Atrophy 16
In 2 sibs with optic atrophy-16 (OPA16; 620629), Fiorini et al. (2023) identified homozygosity for the R258W mutation (608205.0005) in the MECR gene. MECR protein expression was reduced in fibroblasts from the patients. Wildtype MECR and MECR with the R258W mutation were expressed in a yeast knockout for the etr1 gene (the ortholog of MECR) and protein expression of MECR with the R258W mutation was reduced compared to wildtype MECR. In the etr1 yeast mutants, abnormal oxygen consumption and lipoylation of Lat1 and Kgd2 were normalized by expression of wildtype MECR but not MECR with the R258W mutation. Supplementation with lipoic acid in the yeast mutants improved Lat1 and Kgd2 lipoylation and growth after treatment with hydrogen peroxide in the yeast expressing MECR with the R258W mutation.
In a 48-year-old man of Ashkenazi Jewish descent (family A) with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG; 617282), Heimer et al. (2016) identified compound heterozygous mutations in the MECR gene: a c.695G-A transition (c.695G-A, NM_016011.3), resulting in a gly232-to-glu (G232E) substitution at a conserved residue in the cofactor-binding domain, and a c.855T-G transversion, resulting in a tyr285-to-ter (Y285X; 608205.0002) substitution. An unrelated 2-year-old boy of mixed Jewish descent (family B) with the disorder was compound heterozygous for the G232E mutation and a 1-bp insertion (c.830+2_830+3insT; 608205.0003) in intron 7, resulting in a splice site defect and aberrant transcript production. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the 2 families. The c.695G-A mutation was not found in 256 alleles in the Ashkenazi Genome Project or in 206 in-house Ashkenazi Jewish controls, but was found at low frequency in the ExAC database (5 in 121,408). The c.855T-G mutation was not found in any of these 3 databases. The splice site mutation was found in 1 of 256 alleles in the Ashkenazi Genome Project database, in 0 of 210 alleles in the in-house database, and in 10 of 120,664 alleles in the ExAC database. Direct sequencing of these known variants in 2 affected adult brothers of Ashkenazi Jewish descent (family C) identified compound heterozygosity for the same 2 variants found in the 2-year-old boy from family B. In vitro studies showed that the G232E mutation was unable to fully rescue the respiratory defect in a yeast complementation model, consistent with an allele with diminished function; similar yeast complementation studies with the Y285X mutation showed that it resulted in a complete loss of function. Yeast strains transformed with these mutations showed absence of protein lipoylation. Western blot analysis showed no MECR signal with the G232E allele, suggesting that the mutant protein may not be stable, whereas there was evidence that the Y285X allele produced a truncated protein.
For discussion of the c.855T-G transversion (c.855T-G, NM_016011.3) in the MECR gene, resulting in a tyr285-to-ter (Y285X) substitution, that was found in compound heterozygous state in a patient with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG; 617282) by Heimer et al. (2016), see 608205.0001.
For discussion of the a 1-bp insertion in the MECR gene (c.830+2_830+3insT, NM_016011.3) that was found in compound heterozygous state in 3 patients from 2 unrelated families with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG; 617282) by Heimer et al. (2016), see 608205.0001.
In a 7-year-old girl of Tunisian origin (family D) with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG; 617282), Heimer et al. (2016) identified a homozygous c.854A-G transition (c.854A-G, NM_016011.3) in the MECR gene, resulting in a tyr285-to-cys (Y285C) substitution at a conserved residue in the cofactor-binding domain. The mutation was found by Sanger sequencing and segregated with the disorder. The c.854A-G mutation was found in 1 of 120,182 alleles in the ExAC database and was not found in 256 alleles in the Ashkenazi Genome Project database. The residue affected was the same as a nonsense mutation identified in another patient with the disorder (Y285X; 608205.0002).
Dystonia, Childhood-Onset, with Optic Atrophy and Basal Ganglia Abnormalities
In 2 brothers of Anglo-Saxon descent (family E) with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG; 617282), Heimer et al. (2016) identified compound heterozygous mutations in the MECR gene: a c.772C-T transition (c.772-C-T, NM_016011.3), resulting in an arg258-to-trp (R258W) substitution at a conserved residue in the cofactor-binding domain, and a 4-bp deletion (c.247_250del; 608205.0006), resulting in a frameshift and premature termination (Asn83HisfsTer4). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.772C-T mutation was found in 10 of 121,102 alleles in the ExAC database and was not found in 256 alleles in the Ashkenazi Genome Project database; the 4-bp deletion was not found in either database. Patient fibroblasts showed strongly reduced levels of MECR protein and about a 50% decrease in protein lipoylation compared to controls. However, patient cells showed only a modest decrease in activities of complexes I and IV (65-75% of control values).
Optic Atrophy 16
In 2 sibs with optic atrophy-16 (OPA16; 620629), Fiorini et al. (2023) identified homozygosity for the R258W mutation in the MECR gene. The mutation was identified by whole-exome sequencing and segregated with disease in the family. The mutation was reported in the gnomAD database (v2.1.1) with a minor allele frequency of 6.368e-5. MECR protein expression was reduced in fibroblasts from the patients.
For discussion of the 4-bp deletion (c.247_250del, NM_016011.3) in the MECR gene, resulting in a frameshift and premature termination (Asn83HisfsTer4), that was found in compound heterozygous state in 2 brothers with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG; 617282) by Heimer et al. (2016), see 608205.0005.
In a 12-year-old boy, born of consanguineous Chinese parents (family G), with childhood-onset dystonia and basal ganglia abnormalities but without optic atrophy (DYTOABG; 617282), Liu et al. (2021) identified a homozygous c.910G-T transversion (c.910G-T, NM_016011.4) in the MECR gene, resulting in an asp304-to-tyr (D304Y) substitution at a conserved residue in the cofactor binding domain. The mutation was identified by whole-exome sequencing, and the patient's parents and unaffected sib were shown to be mutation carriers. The variant was not present in the 1000 Genomes Project, gnomAD, ExAC, and Exome Sequencing Project databases. MECR protein expression was reduced in patient fibroblasts. Molecular modeling suggested that the D304Y mutation resulted in disturbed protein stability. The authors noted that the patient was treated with lipoic acid from age 10 years, which may explain the absence of optic atrophy.
Fiorini, C., Degiorgi, A., Cascavilla, M. L., Tropeano, C. V., La Morgia, C., Battista, M., Ormanbekova, D., Palombo, F., Carbonelli, M., Bandello, F., Carelli, V., Maresca, A., Barboni, P., Baruffini, E., Caporali, L. Recessive MECR pathogenic variants cause an LHON-like optic neuropathy. J. Med. Genet. 61: 93-101, 2023. [PubMed: 37734847] [Full Text: https://doi.org/10.1136/jmg-2023-109340]
Heimer, G., Keratar, J. M., Riley, L. G., Balasubramaniam, S., Eyal, E., Pietikainen, L. P., Hiltunen, J. K., Marek-Yagel, D., Hamada, J., Gregory, A., Rogers, C., Hogarth, P., and 24 others. MECR mutations cause childhood-onset dystonia and optic atrophy, a mitochondrial fatty acid synthesis disorder. Am. J. Hum. Genet. 99: 1229-1244, 2016. [PubMed: 27817865] [Full Text: https://doi.org/10.1016/j.ajhg.2016.09.021]
Liu, Z., Shimura, M., Zhang, L., Zhang, W., Wang, J., Ogawa-Tominaga, M., Wang, J., Wang, X., Lv, J., Shi, W., Zhang, V. W., Murayama, K., Fang, F. Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy. Mitochondrion 57: 222-229, 2021. [PubMed: 33401012] [Full Text: https://doi.org/10.1016/j.mito.2020.12.014]
Miinalainen, I. J., Chen, Z.-J., Torkko, J. M., Pirila, P. L., Sormunen, R. T., Bergmann, U., Qin, Y.-M., Hiltunen, J. K. Characterization of 2-enoyl thioester reductase from mammals: an ortholog of Ybr026p/Mrf1'p of the yeast mitochondrial fatty acid synthesis type II. J. Biol. Chem. 278: 20154-20161, 2003. [PubMed: 12654921] [Full Text: https://doi.org/10.1074/jbc.M302851200]