Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review presents our current knowledge on the genetic and phenotypic aspects of mitochondrial complex II gene defects. The mutations of the complex II subunits cause two strikingly different group of disorders, revealing a phenotypic dichotomy. Genetic disorders of the mitochondrial respiratory chain are often characterized by hypotonia, growth retardation, cardiomyopathy, myopathy, neuropathy, organ failure, and metabolic derangement. These disorders are transmitted through maternal lineage if the defective gene is located in the mitochondrial genome or may follow a Mendelian pattern if it is in the nucleus. Mitochondrial complex II (succinate:ubiquinone oxidoreductase) is the smallest complex in the respiratory chain and is composed of four subunits encoded by nuclear genes SDHA, SDHB, SDHC, and SDHD. Complex II oxidizes succinate to fumarate in the Krebs cycle and is involved in the mitochondrial electron transport chain. SDHA and SDHB encode the flavoprotein and iron-sulfur proteins, respectively, and SDHC and SDHD encode the two hydrophobic membrane-spanning subunits. While mutations in SDHA display a phenotype resembling other mitochondrial and Krebs cycle gene defects, those in SDHB, SDHC and SDHD cause hereditary paraganglioma. Paraganglioma is characterized by slow-growing vascular tumors of the paraganglionic tissue (i.e., adrenal and extra-adrenal paragangliomas, including those in the head and neck, mediastinum, abdomen, and pheochromocytomas). Paraganglioma caused by SDHD mutations occurs exclusively after paternal transmission, suggesting that genomic imprinting influences gene expression. Association of a mitochondrial gene defect with tumorigenesis expands the phenotypic spectrum of mitochondrial diseases and adds genomic imprinting as a new transmission mode in mitochondrial genetics. The phenotypic features of complex II gene mutations suggest that whereas the catalytic subunit SDHA mutations may compromise the Krebs cycle, those in other structural subunits may affect oxygen sensing and signaling.
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PMID:Phenotypic dichotomy in mitochondrial complex II genetic disorders. 1169 62

MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects' fibroblasts. Lentiviral complementation with wild-type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children.
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PMID:Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy. 2798 24