Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial (CybS), also known assuccinate dehydrogenase complex subunit D (SDHD), is aprotein that in humans is encoded by theSDHDgene. Names previously used for SDHD werePGL andPGL1. Succinate dehydrogenase is an importantenzyme in both thecitric acid cycle and theelectron transport chain.[5][6][7] Hereditary PGL-PCC syndrome is caused by a parental imprint of the SDHD gene. Screening can begin by 6 years of age.
SDHD forms part of the transmembraneprotein dimer withSDHC that anchorsComplex II to the inner mitochondrial membrane. The SDHC/SDHD dimer provides binding sites forubiquinone and water during electron transport at Complex II. Initially,SDHA oxidizessuccinate viadeprotonation at theFAD binding site, leavingfumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the [Fe-S] relay in theSDHB subunit until they reach the [3Fe-4S]iron–sulfur cluster. The electrons are then transferred to an awaitingubiquinone molecule at the active site in the SDHC/SDHD dimer. The O1carbonyl oxygen of ubiquinone is oriented at the active site (image 4) byhydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of subunit C. Following the first single electron reduction step, asemiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone toubiquinol.[11]
Mutations in theSDHDgene can cause familialparaganglioma.[5]Germline mutations inSDHD were first linked to hereditary paraganglioma in 2000.[12] Since then, it has been shown that mutations inSDHB and to a lesser degreeSDHC can cause paranglioma as well as familialpheochromocytoma. Notably, the tumor spectrum is different for the different mutations.SDHB mutations often lead to metastatic disease that is extra-adrenal, whileSDHD mutation related tumors are more typically benign, originating in the head and neck.[13]
The exact mechanism for tumorigenesis is not determined, but it is suspected that malfunction of the SDH complex can cause ahypoxic response in the cell that leads to tumor formation. Mutations in theSDHB,SDHC, SDHD, andSDHAF2 genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.[13] People living at higher altitudes (for example, the Andes mountains) are known to have an increased rate of benign paraganglioma, with the rate of disease increasing with the altitude of the population.
At least five variants in the SDHD gene have been identified in people withCowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by multiple tumor-like growths calledhamartomas and an increased risk of developing certain cancers. When Cowden syndrome and Cowden-like syndrome are caused by SDHD gene mutations, the conditions are associated with a particularly high risk of developingbreast andthyroid cancers. The SDHD gene variants associated with Cowden syndrome and Cowden-like syndrome change single amino acids in the SDHD protein, which likely alters the function of the SDH enzyme. Studies suggest that the defective enzyme could allow cells to grow and divide unchecked, leading to the formation of hamartomas and cancerous tumors. However, researchers are uncertain whether the identified SDHD gene variants are directly associated with Cowden syndrome and Cowden-like syndrome. Some of the variants described above have rarely been found in people without the features of these conditions.[14]
Mutations in theSDHD gene have been found in a small number of people withCarney–Stratakis syndrome, a hereditary form of a cancer of the gastrointestinal tract calledgastrointestinal stromal tumor (GIST). Those with Carney-Stratakis syndrome present with a noncancerous tumor associated with the nervous system called aparaganglioma orpheochromocytoma (a type of paraganglioma). An inherited SDHD gene mutation predisposes an individual to cancer formation. An additional mutation that deletes the normal copy of the gene is needed to cause Carney-Stratakis syndrome. This second mutation, called asomatic mutation, is acquired during a person's lifetime and is present only in tumor cells.[14]
Mitochondrial complex II deficiency (MT-C2D), a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, has also been associated with mutations in theSDHD gene. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifestLeigh syndrome orKearns–Sayre syndrome.[15][16][17]
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