Alternative titles; symbols
HGNC Approved Gene Symbol: SUCLG1
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38) : 2:84,423,528-84,459,280 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p11.2 | Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) | 245400 | Autosomal recessive | 3 |
The SUCLG1 gene encodes the alpha subunit of mitochondrial succinyl CoA synthetase (EC 6.2.1.4) (James et al., 1997).
James et al. (1997) obtained a partial cDNA for SUCLG1. The first 27 amino acids of SUCLG1 are a mitochondrial targeting sequence.
Gross (2015) mapped the SUCLG1 gene to chromosome 2p11.2 based on an alignment of the SUCLG1 sequence (GenBank AF104921) with the genomic sequence (GRCh38).
The alpha subunit of SUCL forms a heterodimer with either of its beta subunits encoded by SUCLA2 (603921) and SUCLG2 (603922), resulting in an ATP/ADP-specific SUCL (A-SUCL) and a GTP/GDP-specific SUCL (G-SUCL). A-SUCL and G-SUCL are located in the mitochondrial matrix, and it is likely that they both catalyze substrate-level phosphorylation in the Krebs cycle (Ostergaard et al., 2007).
In affected members of a consanguineous Pakistani family with autosomal recessive mitochondrial DNA depletion syndrome-9 (MTDPS9; 245400), manifest as encephalomyopathy with methylmalonic aciduria, Ostergaard et al. (2007) identified a homozygous truncating mutation in the SUCLG1 gene (611224.0001). Ostergaard et al. (2007) hypothesized that the mtDNA depletion was likely explained by decreased mitochondrial nucleoside diphosphate kinase (NDPK) activity resulting from the inability of NDPK to form a complex with SUCL. The patients with SUCLG1 mutations had an exceedingly severe phenotype compared to those with SUCLA2 mutations (MTDPS5; 612073). Ostergaard et al. (2007) concluded that the much more severe disorder in patients with SUCLG1 mutations was likely caused by the complete absence of both A-SUCL and G-SUCL, whereas the milder phenotype of patients with SUCLA2 mutations may be explained by the presence of functional G-SUCL. One of the reasons Ostergaard et al. (2007) considered SUCLG1 a candidate gene for fatal infantile lactic acidosis (see 245400) was the excretion of methylmalonate and methylcitrate in these patients, similar to that found in patients with SUCLA2 mutations.
In 3 unrelated patients with mtDNA depletion syndrome-9 and methylmalonic aciduria, Ostergaard et al. (2010) and Rouzier et al. (2010) identified homozygous or compound heterozygous mutations in the SUCLG1 gene (611224.0002-611224.0005). One patient with a slightly milder phenotype and survival to age 12 years was heterozygous for a truncating mutation and had some residual enzyme activity.
In a female child with MTDPS9, Chinopoulos et al. (2019) identified a mutation in the SUCLG1 gene (A209E; 611224.0006) that was heterozygous at the genomic DNA level but homozygous at the transcriptional level. The mutation, which was found by Sanger sequencing, was present in heterozygous state in the father; an unknown ovary donor had been used for in vitro fertilization. Testing in patient fibroblasts showed absence of detectable SUCLG1 protein and decreased mitochondrial substrate-level phosphorylation.
In affected members of a consanguineous Pakistani family with mitochondrial DNA depletion syndrome-9, manifest as encephalomyopathy with methylmalonic aciduria (MTDPS9; 245400), Ostergaard et al. (2007) detected a homozygous deletion of 2 basepairs in exon 2 of the SUCLG1 gene, 113_114delAT. The mutation led to frameshift and a premature stop codon.
In a Swedish patient with mitochondrial DNA depletion syndrome-9, manifest as encephalomyopathy with methylmalonic aciduria (MTDPS9; 245400), Ostergaard et al. (2010) identified a homozygous 215G-C transversion in exon 3 of the SUCLG1 gene, resulting in a gly72-to-ala (G72A) substitution. Each unaffected parent was heterozygous for the mutation, which was not found in 72 controls. The patient presented at age 6 months with failure to thrive, severe axial hypotonia, and lactic acidosis. He showed delayed psychomotor development and died just before age 3 years from metabolic acidosis following a gastrointestinal infection. Western blot analysis showed a severely decreased amount of SUCLG1 in patient fibroblasts. Muscle studies showed moderate mtDNA depletion.
In a patient with encephalomyopathic mitochondrial DNA depletion syndrome-9 with methylmalonic aciduria (MTDPS9; 245400), Rouzier et al. (2010) identified compound heterozygosity for 2 mutations in the SUCLG1 gene: a 509C-G transversion resulting in a pro170-to-arg (P170R) substitution in the CoA ligase domain, and a G-to-C transversion in intron 1, resulting in a splice site mutation and the skipping of exon 1 (611224.0004). The relative mtDNA amount in muscle was 11% of controls, indicating severe mtDNA depletion. Western blot analysis showed complete absence of the SUCLG1 and the SUCLA2 (603921) proteins in patient fibroblasts. These results were consistent with a destabilization of SUCLA2 in the absence of its heterodimer partner SUCLG1. The patient presented at birth with severe axial hypotonia and lactic acidosis. He had delayed psychomotor development and recurrent episodes of acidosis, leading to death at age 1 year.
For discussion of the splice site mutation in the SUCLG1 gene that was found in compound heterozygous state in a patient with encephalomyopathic mitochondrial DNA depletion syndrome-9 with methylmalonic aciduria (MTDPS9; 245400) by Rouzier et al. (2010), see 611224.0003.
In a patient with encephalomyopathic mitochondrial DNA depletion syndrome-9 with methylmalonic aciduria (MTDPS9; 245400), Rouzier et al. (2010) identified a heterozygous 448C-T transition in the SUCLG1 gene, resulting in a gln150-to-ter (Q150X) substitution. A second mutation was not identified, but immunoblot analysis showed decreased amounts of both the SUCLG1 and SUCLA2 proteins in patient fibroblasts compared to controls. These results were consistent with a destabilization of SUCLA2. Although the patient had severe hypotonia, lactic acidosis, and mental retardation, he presented at age 3 months after a period of normal development and was still alive at age 12 years. Skeletal muscle biopsy showed markedly reduced activities for respiratory complexes I and IV, and severe mtDNA depletion (18% of controls). Rouzier et al. (2010) concluded that the slightly milder phenotype in this patient was due to some residual enzyme activity.
In a female child with encephalomyopathic mitochondrial DNA depletion syndrome-9 (MTDPS9; 245400), Chinopoulos et al. (2019) identified a c.626C-A transversion in exon 6 of the SUCLG1 gene, resulting in an ala209-to-glu (A209E) substitution at a highly conserved residue; the mutation was heterozygous at the genomic DNA level but homozygous at the transcriptional level. The mutation, which was identified by Sanger sequencing, was present in heterozygous state in the father; a foreign over ovary donor was used for in vitro fertilization. The allele frequency of the mutation in the ExAC database was 0.0000083. Analysis of cDNA from the patient showed that SUCLG1 with the A209E had homozygous expression, although no second mutation was identified. Testing in patient fibroblasts showed no detectable SUCLG1 protein and decreased mitochondrial substrate-level phosphorylation, consistent with SUCLG1 deficiency. Protein expression of SUCLG2 and SUCLA2 were also decreased in patient fibroblasts, and confocal imaging showed partial mislocalization of SUCLG2.
Chinopoulos, C., Batzios, S., van den Heuvel, L. P., Rodenburg, R., Smeets, R., Waterham, H. R., Turkenburg, M., Ruiter, J. P., Wanders, R. J. A., Doczi, J., Horvath, G., Dobolyi, A., Vargiami, E., Wevers, R. A., Zafeiriou, D. Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. Molec. Genet. Metab. 126: 43-52, 2019. [PubMed: 30470562] [Full Text: https://doi.org/10.1016/j.ymgme.2018.11.009]
Gross, M. B. Personal Communication. Baltimore, Md. 5/29/2015.
James, M., Man, N., Edwards, Y. H., Morris, G. E. The molecular basis for cross-reaction of an anti-dystrophin antibody with alpha-actinin. Biochim. Biophys. Acta 1360: 169-176, 1997. [PubMed: 9128182] [Full Text: https://doi.org/10.1016/s0925-4439(96)00076-2]
Ostergaard, E., Christensen, E., Kristensen, E., Mogensen, B., Duno, M., Shoubridge, E. A., Wibrand, F. Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am. J. Hum. Genet. 81: 383-387, 2007. [PubMed: 17668387] [Full Text: https://doi.org/10.1086/519222]
Ostergaard, E., Schwartz, M., Batbayli, M., Christensen, E., Hjalmarson, O., Kollberg, G., Holme, E. A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria. Europ. J. Pediat. 169: 201-205, 2010. [PubMed: 19526370] [Full Text: https://doi.org/10.1007/s00431-009-1007-z]
Rouzier, C., Le Guedard-Mereuze, S., Fragaki, K., Serre, V., Miro, J., Tuffery-Giraud, S., Chaussenot, A., Bannwarth, S., Caruba, C., Ostergaard, E., Pellissier, J.-F., Richelme, C., Espil, C., Chabrol, B., Paquis-Flucklinger, V. The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein. J. Med. Genet. 47: 670-676, 2010. [PubMed: 20693550] [Full Text: https://doi.org/10.1136/jmg.2009.073445]