Alternative titles; symbols
HGNC Approved Gene Symbol: SDHC
SNOMEDCT: 1187383001, 128755003, 420120006, 722377004; ICD10CM: C49.A;
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:161,314,381-161,363,206 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | Gastrointestinal stromal tumor | 606764 | Autosomal dominant; Isolated cases | 3 |
| Paraganglioma and gastric stromal sarcoma | 606864 | 3 | ||
| Pheochromocytoma/paraganglioma syndrome 3 | 605373 | Autosomal dominant | 3 |
Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms. Complex II in mitochondria has 4 subunits. In order of decreasing molecular weight, they are the flavoprotein (SDHA; 600857), the iron-sulfur protein (SDHB; 185470), and 2 integral membrane proteins: the large cytochrome b, cybL or C, subunit (SDHC) and the small cybS or D subunit (SDHD; 602690). Of the 5 mitochondrial complexes, I to V, complex II is the only one with no subunits encoded by the mitochondrial genome (summary by Hirawake et al., 1997).
Hirawake et al. (1997) deduced the amino acid sequences of the large (cybL, encoded by the SDHC gene) and small (cybS, encoded by the SDHD gene) subunits of cytochrome b in human liver complex II from cDNAs isolated by homology probing with mixed primers for the polymerase chain reaction. The mature cybL and cybS proteins contain 140 and 103 amino acids, respectively, and show little similarity to the amino acid sequences of the subunits from other species, in contrast to the highly conserved features of the flavoprotein (Fp) subunit (encoded by the SDHA gene) and the iron-sulfur protein (Ip) subunit (encoded by the SDHB gene).
Oxidative damage has a role in cellular and organismal aging. Especially toxic are the reactive oxygen byproducts of respiration and other biologic processes. A mutant of the mev1 gene of Caenorhabditis elegans had been found to be hypersensitive to raised oxygen concentrations. Unlike the wildtype, its life span decreased dramatically as oxygen concentrations were increased from 1 to 60%. Strains bearing this mutation accumulated markers of aging (such as fluorescent materials and protein carbonyls) faster than the wildtype. Ishii et al. (1998) showed that mev1 encodes a subunit of the enzyme succinate dehydrogenase cytochrome b, which is a component of complex II of the mitochondrial electron transport chain. They found that the ability of complex II to catalyze electron transport from succinate to ubiquinone was compromised in the mev1 animals. This was thought to cause an indirect increase in superoxide levels, which in turn leads to oxygen hypersensitivity and premature aging. The results indicated that mev1 governs the rate of aging by modulating the cellular response to oxidative stress. This particular mutation in the mev1 mutant was shown to be a missense change resulting in a glycine to glutamic acid substitution in cyt1. The identity of the mev1 gene was established through its sequence homology to bovine succinate dehydrogenase cytochrome b(560) (Cochran et al., 1994). The wildtype gene introduced into the mev1 strain resulted in rescue from the hypersensitivity to raised oxygen concentrations. This was thought to be the first mutation in the SDH cytochrome b subunit to be identified in animals.
SDH Complex Function
In mammalian cells, Spinelli et al. (2021) found that when oxygen reduction is impeded, mitochondrial complex I and dihydroorotate dehydrogenase (DHODH; 126064) can still deposit electrons into the electron transport chain because the accumulation of ubiquinol drives the succinate dehydrogenase complex in reverse to enable electron deposition onto fumarate. Fumarate sustains DHODH and complex I activities by acting as the terminal electron acceptor, maintaining mitochondrial function under oxygen limitation.
Elbehti-Green et al. (1998) found that the SDHC gene contains 6 exons.
By study of Chinese hamster-human somatic cell hybrids in which the hamster parental cell was deficient in succinate dehydrogenase, Mascarello et al. (1980) showed that the presence of human chromosome 1 correlated with restoration of SDH activity. SDH consists of 2 dissimilar peptides of 70,000 and 30,000 Da. These may be determined by separate genes or derived from a single proenzyme. It was presumed that, because it mapped to chromosome 1, the iron sulfur protein subunit gene complemented the deficiency in the mutant. Oostveen et al. (1995) found that in fact it was protein from the bovine SDH3 gene (encoding 1 of the 2 integral membrane proteins) that complemented the hamster mutation. The authors localized the human SDH3 gene to the short arm of chromosome one, within 1 to 2 Mb from the centromere. There are therefore 2 genes for complex II on human chromosome 1. Additionally, Oostveen et al. (1995) stated that Southern analyses of human genomic DNA suggested that there are multiple SDH3 genes or pseudogenes.
By fluorescence in situ hybridization (FISH), Hirawake et al. (1997) mapped the genes for cybL and cybS to 1q21 and 11q23, respectively. Elbehti-Green et al. (1998) confirmed the assignment of the SDHC gene to 1q21 by FISH.
Pheochromocytoma/Paraganglioma Syndrome 3
Because mutations in the SDHD gene, encoding the small subunit of cytochrome b in mitochondrial complex II, had been shown to be a site of mutation causing paraganglioma-1 (PPGL1; 168000), Niemann and Muller (2000) sought mutations in SDHC, SDHA, and SDHB in a family with the nonmaternally imprinted paraganglioma-3 (PPGL3; 605373). They identified a G-to-A transition in exon 1 of SDHC in all affected individuals (602413.0001).
Baysal et al. (2004) described a family with paragangliomas in which an 8,372-bp deletion in the SDHC gene (602413.0003) was transmitted both maternally and paternally, without evidence of genomic imprinting. They also identified the deletion in an unrelated sporadic case. They concluded that hereditary paraganglioma with imprinted transmission is restricted to SDHD among complex II genes.
Paraganglioma and Gastric Stromal Sarcoma
In 2 families with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified 2 different germline mutations in the SDHC gene, respectively (see, e.g., 602413.0004). In 4 other families with the dyad, the authors found germline mutations in the SDHB (see, e.g., 185470.0012 and 185470.0013) and SDHD (602690.0027) genes, respectively. None of the patients had mutations in the KIT (164920) or PDGFRA (173490) genes, which have been associated with gastrointestinal tumors.
Janeway et al. (2011) identified a germline mutation in the SDHC gene (602413.0004) in a 16-year-old girl with sporadic occurrence of gastrointestinal stromal tumor (GIST; 606764).
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human SDHC is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with familial nonchromaffin paragangliomas (PPGL3; 605373), Niemann and Muller (2000) identified a G-to-A transition in exon 1 of the SDHC gene that destroyed the start codon ATG at nucleotide position 958.
Niemann et al. (2003) described a 31-year-old female patient with hypotension and tachycardia. Whole body MRI showed a highly vascularized tumor at the right carotid bifurcation. The diagnosis of paraganglioma (PPGL3; 605373) was confirmed histopathologically in the tumor, and a lymph node showed metastatic tissue. Sequence analysis of the patient's constitutive DNA revealed a heterozygous G-to-T transversion at position +1 of intron 5 of the SDHC gene. An identical germline mutation was observed in the patient's mother. A high resolution computed tomography of the neck, thorax, and abdomen, and urinary excretion of catecholamines in the patient's mother were normal. The mutation led to a deletion of exon 5 and a shift in the reading frame.
In affected members of a family with familial nonchromaffin paragangliomas (PPGL3; 605373) ascertained from an analysis of familial and isolated paraganglioma cases from 2 U.S. otolaryngology clinics, Baysal et al. (2004) identified an 8,372-bp deletion in the SDHC gene, which spanned 2 AluY elements and removed exon 6. The deletion caused PGL3 following both maternal and paternal transmissions in the pedigree and was also detected in an unrelated sporadic case who showed allele sharing with the familial cases at 7 polymorphic markers near SDHC, suggesting a common ancestral origin. These findings confirmed the role of SDHC in both familial and sporadic paragangliomas. The observation of both paternal and maternal disease transmission in PGL3, together with earlier findings, suggested that imprinted transmission in hereditary paraganglioma is restricted to SDHD (602690) among complex II genes.
In a female patient with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a germline G-A transition at the splice donor site in intron 5 (IVS5DS+1) of the SDHC gene. Her unaffected mother also carried the mutation.
Pasini et al. (2008) analyzed cDNA from the 20-year-old female in whom McWhinney et al. (2007) had identified the 405+1G-A mutation in the SDHC gene. They found that the mutant allele resulted in a sequence in which exon 5 was spliced out, causing a frameshift and a stop codon in the 3-prime untranslated region of the gene. DNA analysis of 2 tumor samples showed loss of the normal allele in both, suggesting that the gene defect acts in a recessive manner.
Janeway et al. (2011) identified a germline R242H mutation in a 21-year-old patient with a sporadic gastrointestinal stromal tumor (GIST; 606764).
Baysal, B. E., Willett-Brozick, J. E., Filho, P. A. A., Lawrence, E. C., Myers, E. N., Ferrell, R. E. An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. J. Med. Genet. 41: 703-709, 2004. Note: Erratum: J. Med. Genet. 42: 582 only, 2005. [PubMed: 15342702] [Full Text: https://doi.org/10.1136/jmg.2004.019224]
Cochran, B., Capaldi, R. A., Ackrell, B. A. C. The cDNA sequence of beef heart C(II-3), a membrane-intrinsic subunit of succinate-ubiquinone oxidoreductase. Biochim. Biophys. Acta 1188: 162-166, 1994. [PubMed: 7947903] [Full Text: https://doi.org/10.1016/0005-2728(94)90035-3]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Elbehti-Green, A., Au, H. C., Mascarello, J. T., Ream-Robinson, D., Scheffler, I. E. Characterization of the human SDHC gene encoding one of the integral membrane proteins of succinate-quinone oxidoreductase in mitochondria. Gene 213: 133-140, 1998. [PubMed: 9714607] [Full Text: https://doi.org/10.1016/s0378-1119(98)00186-3]
Hirawake, H., Taniwaki, M., Tamura, A., Kojima, S., Kita, K. Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23. Cytogenet. Cell Genet. 79: 132-138, 1997. [PubMed: 9533030] [Full Text: https://doi.org/10.1159/000134700]
Ishii, N., Fujii, M., Hartman, P. S., Tsuda, M., Yasuda, K., Senoo-Matsuda, N., Yanase, S., Ayusawa, D., Suzuki, K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 394: 694-697, 1998. [PubMed: 9716135] [Full Text: https://doi.org/10.1038/29331]
Janeway, K. A., Kim, S. Y., Lodish, M., Nose, V., Rustin, P., Gaal, J., Dahia, P. L. M., Liegl, B., Ball, E. R., Raygada, M., Lai, A. H., Kelly, L., and 10 others. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc. Nat. Acad. Sci. 108: 314-318, 2011. [PubMed: 21173220] [Full Text: https://doi.org/10.1073/pnas.1009199108]
Mascarello, J. T., Soderberg, K., Scheffler, I. E. Assignment of a gene for succinate dehydrogenase to human chromosome 1 by somatic cell hybridization. Cytogenet. Cell Genet. 28: 121-135, 1980. [PubMed: 6934864] [Full Text: https://doi.org/10.1159/000131520]
McWhinney, S. R., Pasini, B., Stratakis, C. A. Familial gastrointestinal stromal tumors and germ-line mutations. (Letter) New Eng. J. Med. 357: 1054-1056, 2007. [PubMed: 17804857] [Full Text: https://doi.org/10.1056/NEJMc071191]
Niemann, S., Muller, U., Engelhardt, D., Lohse, P. Autosomal dominant malignant and catecholamine-producing paraganglioma caused by a splice donor site mutation in SDHC. Hum. Genet. 113: 92-94, 2003. [PubMed: 12658451] [Full Text: https://doi.org/10.1007/s00439-003-0938-0]
Niemann, S., Muller, U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genet. 26: 268-270, 2000. [PubMed: 11062460] [Full Text: https://doi.org/10.1038/81551]
Oostveen, F. G., Au, H. C., Meijer, P.-J., Scheffler, I. E. A Chinese hamster mutant cell line with a defect in the integral membrane protein C(II-3) of complex II of the mitochondrial electron transport chain. J. Biol. Chem. 270: 26104-26108, 1995. [PubMed: 7592812] [Full Text: https://doi.org/10.1074/jbc.270.44.26104]
Pasini, B., McWhinney, S. R., Bei, T., Matyakhina, L., Stergiopoulos, S., Muchow, M., Boikos, S. A., Ferrando, B., Pacak, K., Assie, G., Baudin, E., Chompret, A., Ellison, J. W., Briere, J.-J., Rustin, P., Gimenez-Roqueplo, A.-P., Eng, C., Carney, J. A., Stratakis, C. A. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Europ. J. Hum. Genet. 16: 79-88, 2008. [PubMed: 17667967] [Full Text: https://doi.org/10.1038/sj.ejhg.5201904]
Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., Kunchok, T., Lewis, C. A., Chandel, N. S., Sabatini, D. M. Fumarate is a terminal electron acceptor in the mammalian electron transport chain. Science 374: 1227-1237, 2021. [PubMed: 34855504] [Full Text: https://doi.org/10.1126/science.abi7495]