Biology:SDHA
From HandWiki
- SDHA converts succinate to fumarate as part of the citric acid cycle. This reaction also converts FAD to FADH2.
- Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S]. This function is part of the Respiratory chain
- Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits.
Clinical significance
Because of the complexity of SDHA's locus, SDHA was rarely analyzed,[1] but in an increasing amount of research, it's been found that mutations in SDHA are pathogenic for a number of conditions, including hereditary pheochromocytoma-paraganglioma (PPGL) syndrome, mitochondrial complex II deficiency, gastrointestinal stromal tumors, Leigh syndrome, dilated cardiomyopathy, and possible relation with pituitary adenomas, adrenal carcinomas, and other neuroendocrine tumors.[2] Hereditary PPGL syndrome associated with mutations in SDHA is called "Paragangliomas 5" with likely lower penetrance than other SDHx mutations.[3]
Bi-allelic mutations in SDHA are known to be pathogenic for infant or early childhood Leigh syndrome, a progressive brain disorder.[4][5][6] It is not known, however, how mutations in the SDHA gene are related to the specific features of Leigh syndrome. There is some link between Leigh syndrome as a phenotype of mitochondrial complex II deficiency, but both can occur without the other as relating to SDHA mutations.[7]
SDHA is a tumour suppressor gene, and heterozygous carriers have an increased risk of paragangliomas as well as pheochromocytomas and renal cancer.[8] Risk management for heterozygous carriers of an SDHA mutation typically involve monitoring via annual urine tests for metanephrines and catecholamines as well as non-radiation imaging such as MRIs. PET scans and radiation imaging are used but should be limited to prevent radiation exposure.[9]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
TCA Cycle edit
- ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78". http://www.wikipathways.org/index.php/Pathway:WP78.
References
- ↑ "Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors". Mod Pathol 26 (2): 289–94. February 2013. doi:10.1038/modpathol.2012.153. PMID 22955521.
- ↑ "SDHA[gene ▶ GRCh37"]. ClinVar. National Library of Medicine. https://www.ncbi.nlm.nih.gov/clinvar/?term=SDHA%5Bgene%5D&redir=gene.
- ↑ "Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study". J Clin Endocrinol Metab 103 (2): 438–445. February 2018. doi:10.1210/jc.2017-01762. PMID 29177515.
"CORRIGENDUM FOR "Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study"". J Clin Endocrinol Metab 103 (5): 2077. May 2018. doi:10.1210/jc.2018-00533. PMID 29538659. - ↑ "Leigh syndrome" (in en). U.S. National Library of Medicine. https://medlineplus.gov/genetics/condition/leigh-syndrome/.
- ↑ "Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II". Molecular Genetics and Metabolism 89 (3): 214–21. November 2006. doi:10.1016/j.ymgme.2006.05.003. PMID 16798039.
- ↑ "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II". American Journal of Medical Genetics. Part A 120A (1): 13–8. July 2003. doi:10.1002/ajmg.a.10202. PMID 12794685.
- ↑ "The genetic basis of isolated mitochondrial complex II deficiency". Mol Genet Metab 131 (1–2): 53–65. 2020. doi:10.1016/j.ymgme.2020.09.009. PMID 33162331.
- ↑ Reference, Genetics Home. "SDHA". https://medlineplus.gov/genetics/gene/sdha/.
- ↑ "SDHA, SDHB or SDHC-related familial paraganglioma-phaeochromocytoma – risk management". eviQ Cancer Treatments Online. Cancer Institute NSW. 22 February 2022. https://www.eviq.org.au/cancer-genetics/adult/risk-management/4066-sdhd-or-sdhaf2-related-familial-paraganglioma.
Further reading
- "Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes". The Biochemical Journal 383 (Pt 2): 237–48. October 2004. doi:10.1042/BJ20040647. PMID 15242332.
- "Single nucleotide polymorphisms in succinate dehydrogenase subunits and citrate synthase genes: association results for impaired spermatogenesis". International Journal of Andrology 30 (3): 144–52. June 2007. doi:10.1111/j.1365-2605.2006.00730.x. PMID 17298551.
- "Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA)". Journal of Neurology, Neurosurgery, and Psychiatry 77 (1): 74–6. January 2006. doi:10.1136/jnnp.2005.067041. PMID 16361598.
- "Housekeeping genes for phylogenetic analysis of eutherian relationships". Molecular Biology and Evolution 23 (8): 1493–503. August 2006. doi:10.1093/molbev/msl027. PMID 16751257.
- "Regulation of succinate-ubiquinone reductase and fumarate reductase activities in human complex II by phosphorylation of its flavoprotein subunit". Proceedings of the Japan Academy. Series B, Physical and Biological Sciences 85 (7): 258–65. 2009. doi:10.2183/pjab.85.258. PMID 19644226. Bibcode: 2009PJAB...85..258T.
- "SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma". Science 325 (5944): 1139–42. August 2009. doi:10.1126/science.1175689. PMID 19628817. Bibcode: 2009Sci...325.1139H.
- "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. January 2006. doi:10.1101/gr.4039406. PMID 16344560.
- "Frataxin interacts functionally with mitochondrial electron transport chain proteins". Human Molecular Genetics 14 (15): 2091–8. August 2005. doi:10.1093/hmg/ddi214. PMID 15961414.
- "Sequence variation in human succinate dehydrogenase genes: evidence for long-term balancing selection on SDHA". BMC Biology 5. March 2007. doi:10.1186/1741-7007-5-12. PMID 17376234.
- "A role for mitochondrial enzymes in inherited neoplasia and beyond". Nature Reviews. Cancer 3 (3): 193–202. March 2003. doi:10.1038/nrc1013. PMID 12612654.
- "Succinate dehydrogenase deficiency in human". Cellular and Molecular Life Sciences 62 (19–20): 2317–24. October 2005. doi:10.1007/s00018-005-5237-6. PMID 16143825.
- "Patients with Leber hereditary optic neuropathy fail to compensate impaired oxidative phosphorylation". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797 (2): 197–203. February 2010. doi:10.1016/j.bbabio.2009.10.003. PMID 19836344.
- "Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression". PLOS ONE 5 (9). September 2010. doi:10.1371/journal.pone.0012862. PMID 20877624. Bibcode: 2010PLoSO...512862H.
- "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II". American Journal of Medical Genetics. Part A 120A (1): 13–8. July 2003. doi:10.1002/ajmg.a.10202. PMID 12794685.
- "Polymorphisms in mitochondrial genes and prostate cancer risk". Cancer Epidemiology, Biomarkers & Prevention 17 (12): 3558–66. December 2008. doi:10.1158/1055-9965.EPI-08-0434. PMID 19064571.
- "Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-beta and retinoic acid-induced cancer cell death". Cell Death and Differentiation 14 (2): 327–37. February 2007. doi:10.1038/sj.cdd.4402004. PMID 16826196.
- "Mitochondrial respiratory chain in the colonic mucosal of patients with ulcerative colitis". Molecular and Cellular Biochemistry 342 (1–2): 111–5. September 2010. doi:10.1007/s11010-010-0474-x. PMID 20440543.
- "Two compound frame-shift mutations in succinate dehydrogenase gene of a Chinese boy with encephalopathy". Brain & Development 36 (5): 394–8. May 2014. doi:10.1016/j.braindev.2013.06.003. PMID 23849264.
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