Sdh gene

SDH is the acronym for "succinate dehydrogenase complex", which is a gene located on chromosome 1p36.13. SDHB encodes a 31.6 kDa enzyme complex of the same name (complex II) of 280 amino acids, which is located in the inner membrane of the mitochondria.

The enzyme complex encoded by the SDH gene, also called succinate-ubiquinone oxidoreductase or complex II, consists of four subunits and catalyzes the oxidation of succinate (succinate + ubiquinone) to fumarate (fumarate + ubiquinol) in the citric acid cycle.

The complex II in mitochondria, of which succinate dehydrogenase is a component, has 4 subunits. In order of decreasing molecular mass these are:

• the flavoprotein (SDHA)
• the iron-sulfur protein (SDHB) and
• the 2 integral membrane proteins SDHC and SDHD

The SDHB subunit is connected to the SDHA subunit at the hydrophilic, catalytic end of the SDH complex, and to the SDHC / SDHD subunits at the hydrophobic end of the complex anchored in the mitochondrial membrane. The SDHB subunit is an iron-sulfur protein with three iron-sulfur clusters. Succinate dehydrogenase is the only membrane-bound protein of the citrate cycle and, as complex II of the respiratory chain, is directly linked to the electron transport chain of the inner mitochondrial membrane. In evolutionary terms, flavoprotein (SDHA) is the oldest subunit.

Mutations in one of the four coding genes of the SDH complex are responsible for various metabolic diseases in humans:

• SDHA: Flavoprotein-UntLeigh syndrome unit, OMIM: 600857 (functional deficit: complex II deficiency)
• SDHB: iron-sulfur protein subunit; OMIM: 185470 (Clinical presentation: pheochromocytoma, paraganglioma, Carney-Stratakis syndrome)
• SDHC: cytochrome b560 subunit; OMIM:602413(paraganglioma, Carney-Stratakis syndrome)
• SDHD: cytochrome b560 subunit; OMIM: 602960(pheochromocytoma, paraganglioma, Carney-Stratakis syndrome, Leigh syndrome; colorectal carcinomas)

The exact pathway leading from the SDHB mutation to tumour development has not yet been clarified. It is possible that succinate accumulation in the cytosol leads to a cascade of false reactions.

1. Astuti D et al (2001) Structural organization of the gene encoding the human iron-sulfur subunit of succinate gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American journal of human genetics. 269 : 49-54.
2. Au HC et al (1995) Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. Genes 159: 249-253.
3. Baysal BE et al (2002) Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. Journal of medical genetics 39: 178-183.
4. Leckschat S et al (1993) The gene for the iron sulfur protein of succinate dehydrogenase (SDH-IP) maps to human chromosomes 1p35-36.1. somatic cell and molecular genetics 19: 505-511.