Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A11
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38) : 17:4,937,130-4,940,046 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.2 | Pheochromocytoma/paraganglioma syndrome 6 | 618464 | Autosomal dominant | 3 |
The oxoglutarate/malate carrier transports 2-oxoglutarate across the inner membranes of mitochondria in an electroneutral exchange for malate or other dicarboxylic acids (summary by Iacobazzi et al., 1992).
Iacobazzi et al. (1992) determined the sequences of the human and bovine mitochondrial 2-oxoglutarate carrier genes from overlapping genomic clones generated by PCR. The coding and protein sequences of the human and bovine genes are 93% and 96.6% identical, respectively. The human protein has 314 amino acids and does not appear to have a processed presequence to target it into mitochondria.
Iacobazzi et al. (1992) demonstrated that the human SLC25A11 gene has 8 exons and spans 2.5 kb.
By fluorescence in situ hybridization, Piccininni et al. (1998) mapped the SLC25A11 gene to 17p13.3.
In a patient with pheochromocytoma/paraganglioma syndrome-6 (PPGL6; 618464), Buffet et al. (2018) identified a germline heterozygous missense mutation in the SLC25A11 gene (P239T; 604165.0001). The mutation, which was found by whole-genome sequencing, was confirmed by Sanger sequencing. Tumor tissue derived from the patient showed homozygosity for the mutation. Subsequent direct Sanger sequencing of the SLC25A11 gene in 639 patients with paragangliomas in whom mutations in other known genes had been excluded identified 6 patients with germline heterozygous SLC25A11 mutations (e.g., 604165.0002-604165.0005). Mutation types included missense, splice site, frameshift, and a silent change; none were found in the dbSNP or ExAC databases. The missense mutations affected highly conserved residues in the signature protein sequence or alpha matrix helix. Five of the 7 patients had metastatic disease. Available tumor tissue derived from the patients showed loss of heterozygosity for SLC25A11. Immunohistochemical studies on the tumor tissue showed absence of the SLC25A11 protein and hypermethylation of DNA and histones compared to controls. Knockdown of the Slc25a11 gene in immortalized mouse chromaffin cells resulted in a hypermethylated and pseudo-hypoxic phenotype, and the cells showed increased adhesion and migration compared to controls, suggesting the acquisition of metastatic properties. These defects could be rescued by wildtype Slc25a11. The cells also showed lower levels of 2-oxoglutarate compared to controls, and treatment with 2-oxoglutarate reversed the migratory phenotype. Succinate levels were normal in these cells and in patient tumor cells, but aspartate and glutamate were increased. Buffet et al. (2018) noted that somatic mutations or copy-number alterations affecting the SLC25A11 gene have been identified in various types of cancer, suggesting that SLC25A11 can act as a tumor-suppressor gene.
In a 46-year-old man (patient 1) with a nonsecreting, nonmetastatic abdominal paraganglioma (PPGL6; 618464), Buffet et al. (2018) identified a germline heterozygous c.715C-A transversion (c.715C-A, NM_003562) in the SLC25A11 gene, resulting in a pro239-to-thr (P239T) substitution at a highly conserved residue. The mutation, which was found by whole-genome sequencing, was confirmed by Sanger sequencing, and was not found in the dbSNP or ExAC databases. Tumor tissue derived from the patient showed homozygosity for the mutation. Immunohistochemical studies on the tumor tissue showed absence of the SLC25A11 protein and hypermethylation of DNA and histones compared to controls. The patient had a significant family history of cancer on the paternal side, but tissue was not available from these individuals.
In a 51-year-old woman (patient 2) with a secreting metastatic abdominal paraganglioma (PPGL6; 618464), Buffet et al. (2018) identified a germline heterozygous c.439A-G transition (c.439A-G, NM_003562) in the SLC25A11 gene, resulting in a met147-to-val (M147V) substitution at a conserved residue. The mutation, which was found by Sanger sequencing, was not present in the dbSNP or ExAC databases. Tumor tissue derived from the patient showed loss of heterozygosity for SLC25A11. Immunohistochemical studies of the tumor tissue showed absence of the SLC25A11 protein and hypermethylation of DNA and histones compared to controls.
In a 32-year-old woman (patient 4) with a nonsecreting, nonmetastatic head and neck paraganglioma (PPGL6; 618464), Buffet et al. (2018) identified a germline heterozygous c.708C-T transition (c.708C-T, NM_003562) in the SLC25A11 gene, resulting in a silent ala236-to-ala (A236A) mutation. The mutation, which was found by Sanger sequencing, was not present in the dbSNP or ExAC databases. Tumor tissue derived from the patient showed loss of heterozygosity for SLC25A11. Immunohistochemical studies of the tumor tissue showed absence of the SLC25A11 protein and hypermethylation of DNA and histones compared to controls.
In a 59-year-old woman (patient 6) with a secreting, metastatic abdominal paraganglioma (PPGL6; 618464), Buffet et al. (2018) identified a germline heterozygous c.421G-A transition (c.421G-A, NM_003562) in the SLC25A11 gene, resulting in a glu141-to-lys (E141K) substitution at a conserved residue. The mutation, which was found by Sanger sequencing, was not present in the dbSNP or ExAC databases. Tumor tissue derived from the patient showed loss of heterozygosity for SLC25A11. Immunohistochemical studies of the tumor tissue showed absence of the SLC25A11 protein and hypermethylation of DNA and histones compared to controls.
In a 74-year-old woman (patient 7) with a secreting metastatic abdominal paraganglioma (PPGL6; 618464), Buffet et al. (2018) identified a germline heterozygous 2-bp deletion (c.107_108del, NM_003562) in the SLC25A11 gene, resulting in a frameshift and premature termination (Thr36SerfsTer71). The mutation, which was found by Sanger sequencing, was not present in the dbSNP or ExAC databases. Tumor tissue derived from the patient showed loss of heterozygosity for SLC25A11. Immunohistochemical studies of the tumor tissue showed absence of the SLC25A11 protein and hypermethylation of DNA and histones compared to controls.
Buffet, A., Morin, A., Castro-Vega, L.-J., Habarou, F., Lussey-Lepoutre, C., Letouze, E., Lefebvre, H., Guilhem, I., Haissaguerre, M., Raingeard, I., Padilla-Girola, M., Tran, T., Tchara, L., Bertherat, J., Amar, L., Ottolenghi, C., Burnichon, N., Gimenez-Roqueplo, A.-P., Favier, J. Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier SLC25A11 gene confer a predisposition to metastatic paragangliomas. Cancer Res. 78: 1914-1922, 2018. [PubMed: 29431636] [Full Text: https://doi.org/10.1158/0008-5472.CAN-17-2463]
Iacobazzi, V., Palmieri, F., Runswick, M. J., Walker, J. E. Sequences of the human and bovine genes for the mitochondrial 2-oxoglutarate carrier. DNA Seq. 3: 79-88, 1992. [PubMed: 1457818] [Full Text: https://doi.org/10.3109/10425179209034000]
Piccininni, S., Iacobazzi, V., Lauria, G., Rocchi, M., Palmieri, F. Assignment of the oxoglutarate carrier gene (SLC20A4) to human chromosome 17p13.3. Cytogenet. Cell Genet. 83: 256-257, 1998. [PubMed: 10072597] [Full Text: https://doi.org/10.1159/000015198]