Alternative titles; symbols
HGNC Approved Gene Symbol: SUCLA2
Cytogenetic location: 13q14.2 Genomic coordinates (GRCh38) : 13:47,942,656-48,001,273 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q14.2 | Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) | 612073 | Autosomal recessive | 3 |
The SUCLA2 gene encodes the beta-subunit of the ADP-forming succinyl-CoA synthetase (SCS-A; EC 6.2.1.5). SCS is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinyl-CoA from succinate and CoA. The reverse reaction occurs in the Krebs cycle, while the forward reaction may produce succinyl-CoA for activation of ketone bodies and heme synthesis. GTP-specific (SCS-G; EC 6.2.1.4) and ATP-specific (SCS-A) isoforms of SCS catalyze GTP-dependent and ATP-dependent reactions, respectively. SCS is composed of an invariant alpha subunit (SUCLG1; 611224) and a beta subunit that determines the enzyme's nucleotide specificity (summary by Johnson et al., 1998).
Using the partial protein sequences of pigeon A-beta and G-beta (603922), the beta subunits of A-SCS and G-SCS, respectively, Johnson et al. (1998) isolated cDNAs from the corresponding pigeon genes. By searching EST databases with the pigeon gene sequences, they identified human and mouse A-beta and G-beta cDNAs. The predicted 411-amino acid human A-beta protein shares 89 to 95% identity with that of pigeon, mouse, and pig, and 38 to 48% identity with the beta subunit of bacterial SCSs. Human A-beta and G-beta are 53% identical. RT-PCR revealed that A-beta is widely expressed, and the levels of A-beta mRNA exceed those of G-beta in nearly all tissues. However, Johnson et al. (1998) noted that enzyme assays using rat and mouse tissues suggested that the relative levels of expression are not directly related to the relative enzymatic activities.
Gross (2015) mapped the SUCLA2 gene to chromosome 13q14.2 based on an alignment of the SUCLA2 sequence (GenBank AF087890) with the genomic sequence (GRCh38).
In a total of 16 patients from the Faroe Islands with encephalomyopathic mitochondrial DNA depletion syndrome-5 and mild methylmalonic aciduria (MTDPS5; 612073), Ostergaard et al. (2007) and Carrozzo et al. (2007) independently identified a homozygous founder mutation in the SUCLA2 gene (603921.0002). Elpeleg et al. (2005) identified a homozygous mutation in the SUCLA2 gene (603921.0001) in 2 first cousins from a consanguineous Muslim family with encephalomyopathy and mitochondrial DNA depletion syndrome, but urinary organic acid profiles were not reported in the 2 patients.
Carrozzo et al. (2007) identified 2 additional SUCLA2 mutations (603921.0003; 603921.0004) in Italian patients with a similar disorder.
In 2 first cousins from a consanguineous Muslim family with encephalomyopathic mitochondrial DNA depletion syndrome-5 (MTDPS5; 612073), Elpeleg et al. (2005) identified a homozygous deletion/insertion in the SUCLA2 gene. There was a complex genomic arrangement at the 3-prime end of exon 6, with a 43-bp deletion encompassing the last 14 bp of exon 6 and the first 29 bp of intron 6, and a 5-bp insertion. Two amplification products were generated: both skipped exon 6, and 1 also lacked the first 74 bp of exon 7. The mutation was not identified in 105 Muslim Arab controls. Skeletal muscle mitochondria from the patients showed significantly decreased activity of complexes I and IV; activities of complexes III and V were less affected. Skeletal muscle DNA from the patients showed a decreased ratio of mtDNA to nuclear DNA (32% of normal values). Urinary organic acids were not evaluated. Elpeleg et al. (2005) postulated a defect in the last step of the mitochondrial deoxyribonucleoside triphosphate (dNTP) salvage pathway.
In a total of 16 patients from the Faroe Islands with encephalomyopathic mtDNA depletion syndrome and mild methylmalonic aciduria (MTDPS5; 612073), Ostergaard et al. (2007) and Carrozzo et al. (2007) independently identified a homozygous G-to-A transition in intron 4 of the SUCLA2 gene, resulting in the skipping of exon 4 and a truncated protein. Carrozzo et al. (2007) referred to the mutation as 534+1G-A. Haplotype analysis indicated a founder effect. The carrier and disease frequencies in this population were estimated to be 2% and 1 in 2,500, respectively.
In 2 unrelated patients with encephalomyopathic mitochondrial DNA depletion with methylmalonic aciduria (MTDPS5; 612073), Carrozzo et al. (2007) identified a homozygous 850C-T transition in exon 7 of the SUCLA2 gene, resulting in a gly118-to-arg (G118R) substitution. Both patients originated from southern Italy. A distantly affected relative of 1 of the patients was found to be compound heterozygous for G118R and R284C (603921.0004).
In a boy with encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria (MTDPS5; 612073), Carrozzo et al. (2007) identified compound heterozygosity for 2 mutations in the SUCLA2 gene: a 352G-A transition in exon 3, resulting in an arg284-to-cys (R284C) substitution, and G118R (603921.0003). The father was from southern Italy and the mother from Romania.
In 2 Iranian cousins from a consanguineous kindred with encephalomyopathic mitochondrial DNA depletion syndrome-5 (MTDPS5; 612073), Jaberi et al. (2013) identified a homozygous c.751G-A transition in the SUCLA2 gene, resulting in an asp251-to-asn (D251N) substitution at a highly conserved residue in the ATP-grasp domain. The mutation was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder, and was not present in 200 ethnically matched control individuals. Molecular modeling suggested that the mutation may cause structural changes that affect protein function. Functional studies were not performed.
Carrozzo, R., Dionisi-Vici, C., Steuerwald, U., Lucioli, S., Deodato, F., Di Giandomenico, S., Bertini, E., Franke, B., Kluijtmans, L. A. J., Meschini, M. C., Rizzo, C., Piemonte, F., Rodenburg, R., Santer, R., Santorelli, F. M., van Rooij, A., Vermunt-de Koning, D., Morava, E., Wevers, R. A. SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia, and deafness. Brain 130: 862-874, 2007. [PubMed: 17301081] [Full Text: https://doi.org/10.1093/brain/awl389]
Elpeleg, O., Miller, C., Hershkovitz, E., Bitner-Glindzicz, M., Bondi-Rubinstein, G., Rahman, S., Pagnamenta, A., Eshhar, S., Saada, A. Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am. J. Hum. Genet. 76: 1081-1086, 2005. [PubMed: 15877282] [Full Text: https://doi.org/10.1086/430843]
Gross, M. B. Personal Communication. Baltimore, Md. 5/29/2015.
Jaberi, E., Chitsazian, F., Ali Shahidi, G., Rohani, M., Sina, F., Safari, I., Malakouti Nejad, M., Houshmand, M., Klotzle, B., Elahi, E. The novel mutation p.Asp251Asn in the beta-subunit of succinate-CoA ligase causes encephalomyopathy and elevated succinylcarnitine. J. Hum. Genet. 58: 526-530, 2013. [PubMed: 23759946] [Full Text: https://doi.org/10.1038/jhg.2013.45]
Johnson, J. D., Mehus, J. G., Tews, K., Milavetz, B. I., Lambeth, D. O. Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes. J. Biol. Chem. 273: 27580-27586, 1998. [PubMed: 9765291] [Full Text: https://doi.org/10.1074/jbc.273.42.27580]
Ostergaard, E., Hansen, F. J., Sorensen, N., Duno, M., Vissing, J., Larsen, P. L., Faeroe, O., Thorgrimsson, S., Wibrand, F., Christensen, E., Schwartz, M. Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain 130: 853-861, 2007. [PubMed: 17287286] [Full Text: https://doi.org/10.1093/brain/awl383]