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Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors

Bora E Baysal1

  • 1Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA. bora.baysal@roswellpark.org

Biochimica Et Biophysica Acta
|January 8, 2013
PubMed

Insights

Germ line mutations in mitochondrial complex II genes predispose to paraganglioma tumors. Genomic imprinting and epigenetic regulation of SDHD are key to understanding this disease and oxygen homeostasis.

Area of Science:

  • Cellular physiology
  • Molecular biology
  • Genetics

Background:

  • Germ line mutations in mitochondrial complex II (succinate dehydrogenase; SDH) genes (SDHB, SDHC, SDHD) and SDHAF2 are linked to paraganglioma development.
  • These tumors exhibit constitutive activation of hypoxia-inducible pathways.
  • A distinct paternal transmission pattern for SDHD and SDHAF2 mutations suggests genomic imprinting.

Purpose of the Study:

  • To investigate the role of genomic imprinting and epigenetic regulation in SDH-related paraganglioma.
  • To explore the mechanisms underlying tissue-specific gene regulation and transmission patterns.
  • To understand the broader implications of SDH gene regulation in oxygen homeostasis.

Main Methods:

  • Analysis of germ line mutations in SDH subunit genes and SDHAF2.
  • Investigation of genomic imprinting patterns, particularly for the SDHD gene.
  • Examination of epigenetic mechanisms, including long-range regulation.
  • Assessment of mRNA editing in peripheral blood mononuclear cells.
  • Analysis of evolutionary selection pressures on SDH genes.

Main Results:

  • Mutations in SDHD and SDHAF2 lead to highly penetrant, multifocal tumors with paternal transmission, while maternal transmission is rare.
  • Evidence supports a long-range epigenetic mechanism for tissue-specific imprinted regulation of the SDHD gene.
  • SDHB mRNA editing and balancing selection on SDHA suggest complex regulatory processes.
  • Diverse epigenetic mechanisms regulate SDH subunit expression, highlighting a dosage-dependent role in oxygen homeostasis.

Conclusions:

  • Genomic imprinting and epigenetic regulation of SDH genes, particularly SDHD, play a critical role in paraganglioma pathogenesis.
  • The dosage-dependent function of SDH in oxygen homeostasis is influenced by complex regulatory mechanisms.
  • Understanding these mechanisms is crucial for comprehending cellular physiology and disease.

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