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Hereditäre Paragangliome

Pathogenese und „Parent-of-Origin-Effekte“

Hereditary paraganglioma

Pathogenesis and parent-of-origin effects


Hereditäre Paragangliome/Phäochromozytome werden autosomal-dominant vererbt. Es lassen sich 3 Formen, PGL1, PGL3 und PGL4 unterscheiden. Sie werden verursacht durch Mutationen in den Genen SDHD, SDHC und SDHB, welche für Komponenten des Komplexes II der mitochondrialen Atmungskette (Succinat-Ubiquinon-Reduktase, SDH) kodieren. Bei allen 3 Formen findet sich „loss of heterozygosity“ (LOH) der Region des mutierten Gens in Tumor-DNA. Dies führt zu Funktionsverlust der SDH, Anhäufung von Succinat sowie Sauerstoffradikalen. Dadurch werden hypoxieabhängige Stoffwechselwege aktiviert, welche zur Tumorbildung führen könnten. Während PGL3 und PGL4 sowohl durch maternal als auch durch paternal vererbte Keimbahnmutationen der Gene SDHC bzw. SDHB verursacht werden, findet sich PGL1 fast ausschließlich bei paternaler Transmission des mutierten SDHD-Gens. Diese Beobachtung lässt sich erklären durch partielle Inaktivierung (Imprinting) des maternalen SDHD-Gens und Induktion hypoxieabhängiger Gene in Paragangliengewebe, wodurch der Verlust des gesamten maternalen Chromosoms 11 durch Non-Disjunction begünstigt werden könnte.


Hereditary paragangliomas/pheochromocytomas are inherited as autosomal dominant traits. Three types, i. e. PGL1, PGL2, and PGL3 can be distinguished. They are caused by mutations of the genes SDHD, SDHC, and SDHB, which encode components of mitochondrial complex II (succinate-ubiquinone reductase, SDH) of the respiratory chain. “Loss of heterozygosity” (LOH) of the region harbouring the disease gene is found in all 3 types of paragangliomas. LOH results in functional loss of SDH, the accumulation of succinate and of reactive oxygen species. As a consequence, hypoxia-dependent metabolic pathways are induced which appear to trigger tumorigenesis. PGL3 and PGL4 can be caused by germ-line mutations in either the paternal or the maternal copy of the respective disease gene, i. e. SDHC and SDHB. In contrast, PGL1 only occurs after paternal transmission of a mutation in SDHD. This observation can be explained by partial inactivation (“imprinting”) of the maternal SDHD-gene and induction of hypoxia-dependent genes, which in turn favour non-disjunction and loss of chromosome 11.

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Müller, U. Hereditäre Paragangliome. medgen 22, 434–438 (2010).

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  • Paragangliom
  • Phäochromozytom
  • Multiple endokrine Neoplasie 2
  • „Loss of heterozygosity“
  • Komplex II der mitochondrialen Atmungskette


  • Paraganglioma
  • Pheochromocytoma
  • Multiple endocrine neoplasia type 2
  • Loss of heterozygosity
  • Electron transport complex II