Mutations in SDHD , a Mitochondrial Complex II Gene, in Hereditary Paraganglioma

Abstract

Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…These include SDHA and SDHB, which form the catalytic domain, and SDHC and SDHD, which anchor the complex to the inner mitochondrial membrane. 1 The assembly factors, SDHAF1 and SDHAF2, ensure both structural and functional integrity of the complex. 2,3 SDH, also called mitochondrial complex II, is the only enzyme involved in both the electron transport chain and the TCA cycle, where it catalyzes the oxidation of succinate to fumarate.…”

“…2,3 SDH, also called mitochondrial complex II, is the only enzyme involved in both the electron transport chain and the TCA cycle, where it catalyzes the oxidation of succinate to fumarate. 1 The TCA cycle is central to the metabolism of sugars, lipids, and amino acids and is a major source of adenosine triphosphate in cells. In addition, the cycle also seems to be involved in tumorigenesis; enzymes of the TCA cycle are involved in the pathogenesis of several tumor types.…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…The complex consists of two subunits (SDHA and SDHB), which protrude into the mitochondrial matrix, and two hydrophobic subunits (SDHC and SDHD), which anchor the catalytic components to the inner mitochondrial membrane and produce the binding site for ubiquinone 59. Mutations in SDHD were the first to be identified as causative in patients with hereditary paragangliomas and later pheochromocytomas, rare neuroendocrine neoplasms of the chromaffin tissue of the adrenal medulla and the parasympathetic tissue of the head and neck paraganglioma, respectively 50. Since the initial discovery of SDHD mutations in 2000, mutations in SDHB and SDHC , and more recently, SDHA and SDHAF2 (encoding the protein responsible for FAD incorporation into SDH) have been identified with the same syndrome 47, 48, 49, 60.…”

Identification of alternatively spliced GRIM-19 mRNA in kidney cancer tissues

“…It has been known that cancer cells have many abnormalities in their mitochondria, and mutations in mitochondrial DNA and nuclear-encoded mitochondrial genes are related to cancers. [7][8][9][10][11] As an example, uterine leiomyomas and RCC have been linked to mutations in fumarate hydratase. 12 Gene associated with Retinoid-Interferon-induced Mortality (GRIM)-19 was originally defined as a cell death regulatory gene, as it is essential for the tumor cell death induced by interferon-b and retinoic acid.…”