Journal Article

SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma

Devilee, Peter, Khalimonchuk, Oleh, Cremers, Cor W.R.J, Bentz, Brandon G, Hao, Huai-Xiang, Schiffman, Joshua D, Gygi, Steven P, Rutter, Jared, Kunst, Henricus, Schraders, Margit, Bayley, Jean-Pierre, Winge, Dennis R, Kremer, Hannie, Dephoure, Noah

2009

Overview

Mammalian mitochondria contain about 1100 proteins, nearly 300 of which are uncharacterized. Given the well-established role of mitochondrial defects in human disease, functional characterization of these proteins may shed new light on disease mechanisms. Starting with yeast as a model system, we investigated an uncharacterized but highly conserved mitochondrial protein (named here Sdh5). Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both the electron transport chain and the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor). Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma, a neuroendocrine tumor previously linked to mutations in genes encoding SDH subunits. Thus, a mitochondrial proteomics analysis in yeast has led to the discovery of a human tumor susceptibility gene.

• Publisher: American Association for the Advancement of Science
• Subject: Adenine / Amino Acid Sequence / Antibodies / Biological and medical sciences / Cell Line / Cell Line, Tumor / chromosomes / Dehydrogenases / electron transport chain / Female / flavin-adenine dinucleotide / Flavin-Adenine Dinucleotide - metabolism / Flavoproteins - metabolism / Fluorescence / Genes / Genetic mutation / germ cells / Germ-Line Mutation / Haplotypes / human diseases / Humans / Inheritance Patterns / loss-of-function mutation / Male / Medical sciences / Mitochondria / Mitochondria - metabolism / Mitochondrial Proteins - chemistry / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Molecular Sequence Data / Nervous system diseases / Neurology / Oxygen Consumption / Paraganglioma - genetics / Pedigree / Plasmids / protein subunits / Protein Subunits - metabolism / proteins / Proteomics / Saccharomyces cerevisiae - genetics / Saccharomyces cerevisiae - growth & development / Saccharomyces cerevisiae - metabolism / Saccharomyces cerevisiae Proteins - chemistry / Saccharomyces cerevisiae Proteins - genetics / Saccharomyces cerevisiae Proteins - metabolism / succinate dehydrogenase (quinone) / Succinate Dehydrogenase - metabolism / tricarboxylic acid cycle / Tumors / Tumors of the nervous system. Phacomatoses / Yeasts