Alternative titles; symbols
HGNC Approved Gene Symbol: SDHA
Cytogenetic location: 5p15.33 Genomic coordinates (GRCh38): 5:218,320-268,746 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p15.33 | Cardiomyopathy, dilated, 1GG | 613642 | Autosomal recessive | 3 |
| Mitochondrial complex II deficiency, nuclear type 1 | 252011 | Autosomal recessive | 3 | |
| Neurodegeneration with ataxia and late-onset optic atrophy | 619259 | Autosomal dominant | 3 | |
| Pheochromocytoma/paraganglioma syndrome 5 | 614165 | Autosomal dominant | 3 |
Complex II of the mitochondrial respiratory chain, also known as succinate dehydrogenase or succinate:ubiquinone oxidoreductase (EC 1.3.5.1), consists of 4 nuclear-encoded polypeptides. In order of decreasing molecular mass, these are the flavoprotein subunit (SDHA), the iron sulfur protein subunit (SDHB; 185470), and the integral membrane protein subunits SDHC (602413) and SDHD (602690) (summary by Hirawake et al., 1994).
Hirawake et al. (1994) isolated a cDNA corresponding to the flavoprotein subunit of SDH from a human liver cDNA library. The deduced 621-amino acid protein has a molecular mass of approximately 68 kD and shows high homology to the bovine heart flavoprotein subunit.
Morris et al. (1994) cloned and sequenced the flavoprotein subunit of human heart SDH.
Burnichon et al. (2010) determined that the SDHA gene is highly polymorphic.
SDH Complex Function
Mills et al. (2018) showed that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signaling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. Mills et al. (2018) identified a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase suppresses thermogenesis. Finally, Mills et al. (2018) showed that pharmacologic elevation of circulating succinate drives UCP1 (113730)-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance.
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.
By fluorescence in situ hybridization, Bourgeron et al. (1995) demonstrated that the flavoprotein subunit gene is duplicated in the human genome, present on chromosomes 3q29 and 5p15, with only the gene on chromosome 5 expressed in human/hamster somatic cell hybrids. The gene on chromosome 3q29 is a pseudogene.
Mitochondrial Complex II Deficiency, Nuclear Type 1
In 2 sibs with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011) presenting as Leigh syndrome (see 256000), Bourgeron et al. (1995) identified a homozygous mutation in the SHDA gene (R554W; 600857.0001). Bourgeron et al. (1995) claimed that this was the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans.
In a patient with MC2DN1 manifesting as Leigh syndrome, Parfait et al. (2000) identified compound heterozygous 2 mutations in the SDHA gene (A524V, 600857.0002; M1L, 600857.0003).
In a female infant who died at 5.5 months of age following a respiratory infection and was found to have MC2DN1, Van Coster et al. (2003) identified homozygosity for a missense mutation in the SDHA gene (G555E; 600857.0004). The authors noted that the patient died in infancy before signs of Leigh syndrome could develop.
Pagnamenta et al. (2006) reported a 10-year-old Palestinian boy with MC2DN1 manifest as Leigh syndrome in whom they identified homozygosity for the G555E mutation in the SDHA gene. Pagnamenta et al. (2006) noted that the patient previously reported by Van Coster et al. (2003) with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation.
Dilated Cardiomyopathy 1GG
In 15 Bedouin patients from a single tribe with neonatal dilated cardiomyopathy (CMD1GG; 613642), Levitas et al. (2010) identified homozygosity for the G555E mutation in the SDHA gene. The patients all had a normal neuromuscular examination at presentation and follow-up, and psychomotor development was appropriate for age. Brain MRI was performed in 2 patients and showed no focal lesions.
Pheochromocytoma/Paraganglioma Syndrome 5
In a woman with a catecholamine-secreting extraadrenal paraganglioma (PPGL5; 614165), Burnichon et al. (2010) identified a heterozygous germline mutation in the SDHA gene (R589W; 600857.0005). Tumor tissue showed loss of heterozygosity (LOH) at the SDHA locus. In vitro functional expression studies in the yeast homolog showed that the mutation resulted in a loss of SDH activity and rendered the mutant SDHA protein more susceptible to proteolysis. Studies of tumor tissue from the patient showed lack of SDHA and SDHB (185470) expression. Transcriptome analysis of the patient's tumor showed a similar pattern as that of other SDH-subunit mutated paraganglioma tumors, including stabilization of HIF1A (603348), consistent with activation of a pseudohypoxic pathway and angiogenesis. The findings indicated that SDHA, like other SDH subunits, can act as a tumor suppressor gene. Analysis of a large series of paragangliomas and pheochromocytomas found LOH at the SDHA locus in only 9 (4.5%) of 202 tumors, suggesting that it is an infrequent event.
Korpershoek et al. (2011) found that 7 of 316 pheochromocytomas and paragangliomas, including the SDHA-mutated paraganglioma described by Burnichon et al. (2010), were negative for SDHA immunostaining. All patients were found to carry a heterozygous mutation in the SDHA gene (600857.0005; 600857.0008-600857.0009), and all tumor tissue showed LOH for the wildtype SDHA allele. None of the patients had a family history of the disorder. All tumors were also negative for SDHB immunostaining, suggesting that impaired complex II formation results in SDHB degradation. The findings established SDHA as a tumor-suppressor gene.
Neurodegeneration with Ataxia and Late-Onset Optic Atrophy
In 2 adult sisters with neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA; 619259), who were originally reported by Taylor et al. (1996), Birch-Machin et al. (2000) identified a heterozygous missense mutation in the SDHA gene (R451C; 600857.0011). The mutation, which was found by direct sequencing, was not found in an unaffected sister or in 80 control samples. In vitro functional expression studies in E. coli showed almost no mitochondrial complex II or SDH activity compared to controls; there was decreased protein expression at the membrane. The evidence suggested that the mutation interfered with association of the FAD cofactor. Patient myoblasts showed normal membrane content of SDHA immunoreactive protein, but complex II and SDH activity were 50% of normal values.
In 3 affected members of a 2-generation family with NDAXOA, Courage et al. (2017) identified a heterozygous R451C mutation in the SDHA gene. Molecular modeling predicted that the mutation interfered with succinate binding, causing a loss of succinate dehydrogenase activity. Functional studies of the variant were not performed, but patient cells showed about a 50% decrease in complex II activity. The patients in this family also developed cardiomyopathy, including an infant who died at 7 months of age.
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 SDHA is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
High similarity between yeast and human mitochondria allows functional genomic study of S. cerevisiae to be used in identifying human genes involved in disease (Foury, 1997). A considerable number of heritable disorders had been attributed to defects in known nuclear-encoded mitochondrial proteins in humans. Many mitochondrial diseases remained unexplained, however, in part because only 40 to 60% of the presumed 700 to 1,000 proteins involved in mitochondrial function and biogenesis had been identified (Wallace, 1999). Steinmetz et al. (2002) applied a systematic functional screen using the preexisting whole-genome pool of yeast deletion mutants to identify mitochondrial proteins. A large number of measurements of strain fitness identified 466 genes whose deletions impaired mitochondrial respiration, 265 of which were new. The approach gave higher selection than other systematic approaches, including 5-fold greater selection than gene expression analysis. To apply these advantages to human disorders involving mitochondria, human orthologs were identified and linked to heritable diseases using genomic map positions. Steinmetz et al. (2002) identified 22 human mitochondria-related genes that give rise to disease and for which there was an associated quantitative deletion phenotype in yeast. They also identified new human candidate genes as the possible basis of mitochondria-related diseases, including spastic paraplegia-5A (270800), Friedreich ataxia-2 (FRDA2; 601992), and 2 forms of optic atrophy: OPA2 (311050) and OPA4 (605293). Deletion in the yeast homolog suggested genes as the basis of the human disorder.
In 2 sibs with complex II mitochondrial respiratory chain deficiency nuclear type 1 (MC2DN1; 252011) presenting as Leigh syndrome (see 256000), Bourgeron et al. (1995) demonstrated a 1684C-T transition in the succinate dehydrogenase flavoprotein subunit gene in a CpG dinucleotide, resulting in an arg554-to-trp (R554W) substitution in a conserved domain of the protein. Functional expression studies in an SDH-negative yeast strain transformed with the mutant R554W protein showed decreased catalytic activity (approximately 50% of controls). The mutation was absent from 120 controls. The sibs were originally described by Bourgeois et al. (1992).
In a girl with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011) presenting as Leigh syndrome (see 256000), Parfait et al. (2000) identified compound heterozygous mutations in the SDHA gene: a C-to-T transition, resulting in an ala524-to-val (A524V) substitution, and an A-to-C transversion, resulting in a met1-to-leu (M1L; 600857.0003) substitution.
For discussion of the met1-to-leu (M1L) mutation in the SDHA gene that was found in compound heterozygous state in a patient with complex II deficiency nuclear type 1 (MC2DN1; 252011) by Parfait et al. (2000), see 600857.0002.
Mitochondrial Complex II Deficiency, Nuclear Type 1
In a patient with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011), born of first-cousin parents, Van Coster et al. (2003) identified a homozygous 1664G-A transition in exon 13 of the SDHA gene, resulting in a gly555-to-glu (G555E) substitution. The patient died at 5.5 months of age following a respiratory infection. Crossreacting material (CRM) for flavoprotein as well as iron-containing protein was decreased, and CRM for the entire complex II was reduced even more. The observation prompted speculation of a labile interaction between iron-containing protein and flavoprotein polypeptides and of a key role of the amino acid at position 555 in the interacting domain. The observation pointed to the fragile equilibrium of intermediate metabolism in infants with complex II deficiency.
In a 10-year-old boy with relatively mild Leigh syndrome and isolated deficiency of mitochondrial complex II and relatively mild Leigh syndrome, who was born of consanguineous Palestinian parents, Pagnamenta et al. (2006) identified homozygosity for the G555E mutation in the SDHA gene. The unaffected parents were heterozygous for the mutation, which was not found in 60 controls. The authors noted that the patient previously reported by Van Coster et al. (2003) with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation. Pagnamenta et al. (2006) stated that both patients had comparable activities and stability of mitochondrial respiratory chain enzymes. Biochemical studies of cultured fibroblasts showed that the size of the band corresponding to the partially assembled complex II differed slightly between the 2 patients; however, their phenotypic variability remained unexplained.
Dilated Cardiomyopathy 1GG
In 15 Bedouin patients from a single tribe with neonatal dilated cardiomyopathy (CMD1GG; 613642), including 13 patients from 2 consanguineous families and 2 sporadic patients, Levitas et al. (2010) identified homozygosity for the G555E mutation in the SDHA gene. The patients all had a normal neuromuscular examination at presentation and follow-up, and psychomotor development was appropriate for age. Brain MRI was performed in 2 patients and showed no focal lesions. Levitas et al. (2010) noted that the unaffected father of 1 of the patients was also homozygous for the G555E mutation, and he had 3 sibs who had died at a young age due to cardiovascular failure. Evaluation of other subunits of complex II (SDHB, 185470; SDHD, 602690) and a candidate modifier gene (SDHAF1; 612848) showed no difference between the father, his affected son, and other Bedouin patients. The enzymatic activity of the father's complex II was decreased by 42% and was more similar to that of the other patients than to the heterozygous mother or controls. Levitas et al. (2010) stated that they did not have an explanation for the normal phenotype of the father.
In a woman with a catecholamine-secreting extraadrenal paraganglioma (PPGL5; 614165), Burnichon et al. (2010) identified a heterozygous germline 1765C-T transition in the SDHA gene, resulting in an arg589-to-trp (R589W) substitution at a highly conserved residue. The mutation was not found in 740 control chromosomes. Tumor tissue showed loss of heterozygosity (LOH) at the SDHA locus. In vitro functional expression studies in the yeast homolog showed that the mutation resulted in a loss of SDH activity and rendered the mutant SDHA protein more susceptible to proteolysis. Studies of tumor tissue from the patient showed lack of SDHA and SDHB (185470) expression. Transcriptome analysis of the patient's tumor showed a similar pattern as that of other SDH-subunit mutated paraganglioma tumors, including stabilization of HIF1A (603348), consistent with activation of a pseudohypoxic pathway and angiogenesis. The findings indicated that SDHA, like other SDH subunits, can act as a tumor suppressor gene.
In a boy with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011) manifest as cardiomyopathy and leukoencephalopathy, Alston et al. (2012) identified compound heterozygosity for 2 mutations in the SDHA gene: a 1523C-T transition in exon 11 resulting in a thr508-to-ile (T508I) substitution, and a 1526C-T transition in exon 11 resulting in a ser509-to-leu (S509L; 600857.0007) substitution. Both mutations occurred at highly conserved residues within the catalytic flavoprotein subunit of the complex. Each unaffected parent was heterozygous for 1 of the mutations.
For discussion of the ser509-to-leu (S509L) mutation in the SDHA gene that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011) by Alston et al. (2012), see 600857.0006.
In 4 Dutch patients with paragangliomas (PPGL5; 614165), Korpershoek et al. (2011) identified a heterozygous germline c.91C-T transition (c.91C-T, NM_004168) in the SDHA gene, resulting in an arg31-to-ter (R31X) substitution. The mutation was found in 2 (0.3%) of 692 Dutch controls. All corresponding tumors showed loss of heterozygosity for SDHA and lack of SDHA and SDHB (185470) immunostaining.
In a French patient with paragangliomas (PGL5; 614165), Korpershoek et al. (2011) identified a heterozygous germline c.1753C-T transition (c.1753C-T, NM_004168) in the SDHA gene, resulting in an arg585-to-trp (R585W) substitution. The mutation was found in 1 (0.1%) of 972 Dutch controls. Tumor tissue showed loss of heterozygosity for SDHA and lack of SDHA and SDHB (185470) immunostaining.
In a 20-year-old woman with paragangliomas (PGL5; 614165), Welander et al. (2013) identified a heterozygous germline c.223C-T transition in the SDHA gene, resulting in an arg75-to-ter (R75X) substitution. Tumor tissue showed absence of SDHA and SDHB (185470) immunostaining.
In 2 adult sisters with neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA; 619259), who were originally reported by Taylor et al. (1996), Birch-Machin et al. (2000) identified a heterozygous c.1375C-T transition in the SDHA gene, resulting in an arg408-to-cys (R408C) substitution in a highly conserved region (this numbering is equivalent to R451C; see Courage et al., 2017). The mutation, which was found by direct sequencing, was not found in an unaffected sister or in 80 control samples. In vitro functional expression studies in E. coli showed almost no mitochondrial complex II or SDH activity compared to controls; there was decreased protein expression at the membrane. The evidence suggested that the mutation interfered with association of the FAD cofactor. Patient myoblasts showed normal membrane content of SDHA immunoreactive protein, but complex II and SDH activity were 50% of normal values.
In 3 affected members of a 2-generation family with NDAXOA, Courage et al. (2017) identified a heterozygous c.1351C-T transition in exon 10 of the SDHA gene, resulting in an arg451-to-cys (R451C) substitution. The authors noted that this is the same mutation as that identified by Birch-Machin et al. (2000). Molecular modeling predicted that the mutation interfered with succinate binding, causing a loss of succinate dehydrogenase activity. Functional studies of the variant were not performed, but patient cells showed about a 50% decrease in complex II activity. The patients in this family also developed cardiomyopathy, including an infant who died at 7 months of age.
Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W. Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J. Med. Genet. 49: 569-577, 2012. [PubMed: 22972948] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101146]
Birch-Machin, M. A., Taylor, R. W., Cochran, B., Ackrell, B. A. C., Turnbull, D. M. Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann. Neurol. 48: 330-335, 2000. [PubMed: 10976639]
Bourgeois, M., Goutieres, F., Chretien, D., Rustin, P., Munnich, A., Aicardi, J. Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome. Brain Dev. 14: 404-408, 1992. [PubMed: 1492653] [Full Text: https://doi.org/10.1016/s0387-7604(12)80349-4]
Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genet. 11: 144-149, 1995. [PubMed: 7550341] [Full Text: https://doi.org/10.1038/ng1095-144]
Burnichon, N,, Briere, J.-J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., Jouanno, E., Jeunemaitre, X., Benit, P., Tzagoloff, A., Rustin, P., Bertherat, J., Favier, J., Gimenez-Roqueplo, A.-P. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Molec. Genet. 19: 3011-3020, 2010. [PubMed: 20484225] [Full Text: https://doi.org/10.1093/hmg/ddq206]
Courage, C., Jackson, C. B., Hahn, D., Euro, L., Nuoffer, J.-M., Gallati, S., Schaller, A. SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement. Am. J. Med. Genet. 173A: 225-230, 2017. [PubMed: 27683074] [Full Text: https://doi.org/10.1002/ajmg.a.37986]
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]
DiMauro, S., Schon, E. A. Nuclear power and mitochondrial disease. Nature Genet. 19: 214-215, 1998. [PubMed: 9662387] [Full Text: https://doi.org/10.1038/883]
Foury, F. Human genetic diseases: a cross-talk between man and yeast. Gene 195: 1-10, 1997. [PubMed: 9300813] [Full Text: https://doi.org/10.1016/s0378-1119(97)00140-6]
Hirawake, H., Wang, H., Kuramochi, T., Kojima, S., Kita, K. Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria. J. Biochem. 116: 221-227, 1994. [PubMed: 7798181] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a124497]
Korpershoek, E., Favier, J., Gaal, J., Burnichon, N., van Gessel, B., Oudijk, L., Badoual, C., Gadessaud, N., Venisse, A., Bayley, J.-P., van Dooren, M. F., de Herder, W. W., Tissier, F., Plouin, P.-F., van Nederveen, F. H., Dinjens, W. N. M., Gimenez-Roqueplo, A.-P., de Krijger, R. R. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J. Clin. Endocr. Metab. 96: E1472-E1476, 2011. Note: Electronic Article. [PubMed: 21752896] [Full Text: https://doi.org/10.1210/jc.2011-1043]
Levitas, A., Muhammad, E., Harel, G., Saada, A., Caspi, V. C., Manor, E., Beck, J. C., Sheffield, V., Parvari, R. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. Europ. J. Hum. Genet. 18: 1160-1165, 2010. [PubMed: 20551992] [Full Text: https://doi.org/10.1038/ejhg.2010.83]
Mills, E. L., Pierce, K. A., Jedrychowski, M. P., Garrity, R., Winther, S., Vidoni, S., Yoneshiro, T., Spinelli, J. B., Lu, G. Z., Kazak, L., Banks, A. S., Haigis, M. C., Kajimura, S., Murphy, M. P., Gygi, S. P., Clish, C. B, Chouchani, E. T. Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature 560: 102-106, 2018. [PubMed: 30022159] [Full Text: https://doi.org/10.1038/s41586-018-0353-2]
Morris, A. A. M., Farnsworth, L., Ackrell, B. A. C., Turnbull, D. M., Birch-Machin, M. A. The cDNA sequence of the flavoprotein subunit of human heart succinate dehydrogenase. Biochim. Biophys. Acta 1185: 125-128, 1994. [PubMed: 8142412] [Full Text: https://doi.org/10.1016/0005-2728(94)90203-8]
Pagnamenta, A. T., Hargreaves, I. P., Duncan, A. J., Taanman, J.-W., Heales, S. J., Land, J. M., Bitner-Glindzicz, M., Leonard, J. V., Rahman, S. Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II. Molec. Genet. Metab. 89: 214-221, 2006. [PubMed: 16798039] [Full Text: https://doi.org/10.1016/j.ymgme.2006.05.003]
Parfait, B., Chretien, D., Rotig, A., Marsac, C., Munnich, A., Rustin, P. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum. Genet. 106: 236-243, 2000. [PubMed: 10746566] [Full Text: https://doi.org/10.1007/s004390051033]
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]
Steinmetz, L. M., Scharfe, C., Deutschbauer, A. M., Mokranjac, D., Herman, Z. S., Jones, T., Chu, A. M., Giaever, G., Prokisch, H., Oefner, P. J., Davis, R. W. Systematic screen for human disease genes in yeast. Nature Genet. 31: 400-404, 2002. [PubMed: 12134146] [Full Text: https://doi.org/10.1038/ng929]
Taylor, R. W., Birch-Machin, M. A., Schaefer, J., Taylor, L., Shakir, R., Ackrell, B. A. C., Cochran, B., Bindoff, L. A., Jackson, M. J., Griffiths, P., Turnbull, D. M. Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia. Ann. Neurol. 39: 224-232, 1996. [PubMed: 8967754] [Full Text: https://doi.org/10.1002/ana.410390212]
Van Coster, R., Seneca, S., Smet, J., Van Hecke, R., Gerlo, E., Devreese, B., Van Beeumen, J., Leroy, J. G., De Meirleir, L., Lissens, W. Homozygous gly555-to-glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II. Am. J. Med. Genet. 120A: 13-18, 2003. [PubMed: 12794685] [Full Text: https://doi.org/10.1002/ajmg.a.10202]
Wallace, D. C. Mitochondrial diseases in man and mouse. Science 283: 1482-1488, 1999. [PubMed: 10066162] [Full Text: https://doi.org/10.1126/science.283.5407.1482]
Welander, J., Garvin, S., Bohnmark, R., Isaksson, L., Wiseman, R. W., Soderkvist, P., Gimm, O. Germline SDHA mutation detected by next-generation sequencing in a young index patient with large paraganglioma. J. Clin. Endocr. Metab. 98: E1379-E1380, 2013. Note: Electronic Article. [PubMed: 23750034] [Full Text: https://doi.org/10.1210/jc.2013-1963]