An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study

Steenweg, Marjan E.; Jakobs, Cornelis; Errami, Abdellatif; Dooren, Silvy J.M. van; Bartolomé, Maria T. Adeva; Aerssens, Peter; Augoustides-Savvapoulou, Persephone; Barić, Ivo; Baumann, Matthias; Bonafé, Luisa; Chabrol, B.; Clarke, Joe T.R.; Clayton, Peter T.; Çöker, Mahmut; Cooper, Sarah; Falik‐Zaccai, Tzipora C.; Gorman, Mark; Hahn, Andreas; Hasanoğlu, Alev; King, Mary D.; Klerk, Hans B.C. de; Korman, Stanley H.; Lee, Céline; Lund, Allan M.; Mejaški-Bošnjak, Vlatka; Pascual-Castroviejo, I; Raadhyaksha, Aparna; Rootwelt, Terje; Roubertie, Agathe; Ruiz-Falcó, María Luz; Scalais, Emmanuel; Schimmel, Ulf; Seijo-Martínez, Manuel; Suri, Mohnish; Sykut-Cegielska, Jolanta; Trefz, Friedrich K.; Uziel, Graziella; Valayannopoulos, Vassili; Vianey‐Saban, Christine; Vlaho, S; Vodopiutz, Julia; Wajner, Moaçir; Walter, John H.; Walter-Derbort, Claudia; Yapıcı, Zühal; Zafeiriou, Dimitrios I.; Spreeuwenberg, Marieke; Celli, Jacopo; Dunnen, Johan T. den; Knaap, Marjo S. van der; Salomons, Gajja S.

doi:10.1002/humu.21197

Cited by 110 publications

(95 citation statements)

References 41 publications

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“…2HG is prevented from accumulating in cells by the actions of two enzymes-(D)-2HG and (L)-2HG dehydrogenase (2HGDH)-that convert (R)-2HG and (S)-2HG, respectively, back to 2OG (Struys et al 2005a;Steenweg et al 2010). There is currently no known physiologic role for either enantiomer in normal metabolism.…”

Section: Mutant Idh-derived (R)-2hg Is An Oncometabolitementioning

confidence: 99%

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

2013

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Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similarHere we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.Cellular metabolism has been hypothesized to play a central role in cancer since the observation made almost a century ago by Otto Warburg (Warburg 1956) that cancer cells preferentially generate energy by metabolizing glucose to lactate. Even in the presence of oxygen, cancer cells switch from generating ATP by the highly energy-efficient process of oxidative phosphorylation to the much less efficient process of glycolysis (Vander Heiden et al. 2009;Dang 2012). Why this switch occurs has long been a mystery, although the observation that normal cells use ''aerobic glycolysis'' during periods of increased proliferation supports the hypothesis that this metabolic switch is an important feature of rapidly dividing cells (Locasale and Cantley 2011;Lunt and Vander Heiden 2011). Recent work suggests that aerobic glycolysis facilitates cellular transformation by producing the high levels of glycolytic intermediates that proliferating cells need for the biosynthesis of lipids, amino acids, and nucleic acids. Moreover, metabolic reprogramming appears to be sufficient to mediate tumorigenesis in some systems (Lyssiotis and Cantley 2012;Sebastian et al. 2012). Nevertheless, whether altered cellular metabolism is a cause of cancer or merely an adaptive response of cancer cells in the face of accelerated cell proliferation is still a topic of some debate.The recent identification of cancer-associated mutations in three metabolic enzymes suggests that altered cellular metabolism can indeed be a cause of some cancers (Pollard et al. 2003;King et al. 2006;Raimundo et al. 2011). Two of these enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are bone fide tumor suppressors, and loss-of-function mutations in FH and SDH have been identified in various cancers, including renal cell carcinomas and paragangliomas. The third mutated enzyme, isocitrate dehydrogenase (IDH), is a more complicated case. Mutations in two isoforms of IDH, IDH1 and IDH2, are common in a diverse array of cancers, including gliomas and acute myelogenous leukemia (AML) (Dang et al. 2010). The mutant enzymes are not catalytically inactive. Rather, the cancer-associated mutations alter the catalytic activity of the enzymes such that they produce high levels of a metabolite, (R)-2-hydroxyglutarate [(R)-2HG], which is normally ...

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Section: Mutant Idh-derived (R)-2hg Is An Oncometabolitementioning

confidence: 99%

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

2013

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“…Genetic characterization has shown that 50% of the D-2-HGA population and the majority of L-2-HGA patients harbor pathogenic mutations in D2HGDH and L2HGDH genes, respectively (1)(2)(3). The other half of D-2-HGA patients have a gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2) at the residue of R140 (R140Q), which leads to abnormally high accumulation of D-2-HG (4).…”

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L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Ma¹,

Sun²,

Jiang³

et al. 2017

Molecular and Cellular Biology

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L-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of L-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.KEYWORDS L2HGDH, 2-HG, leukoencephalopathy, gliosis, neurodegeneration T he rare, autosomal recessive neurometabolic disorders D-2-hydroxyglutaric aciduria (D-2-HGA) and L-2-hydroxyglutaric aciduria (L-2-HGA) are characterized by the accumulation of D-2-hydroxyglutarate (D-2-HG) and L-2-hydroxyglutarate (L-2-HG), respectively, in body fluids. Genetic characterization has shown that 50% of the D-2-HGA population and the majority of L-2-HGA patients harbor pathogenic mutations in D2HGDH and L2HGDH genes, respectively (1-3). The other half of D-2-HGA patients have a gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2) at the residue of R140 (R140Q), which leads to abnormally high accumulation of D-2-HG (4). Based on phenotypic severity in patients, D-2-HGA is classified as mild type I (D2HGDH mutation) and severe type II (IDH2 mutation) (4, 5). Of note, 2-HG concentrations are 2-to 8-fold higher for type II D-2-HGA than type I D-2-HGA patients (4, 6, 7), suggesting that

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“…A doença tem manifestação durante a infância, mas pode se apresentar na idade adulta com fenótipos mais brandos 7,30,31 . O bloqueio metabólico presente nesses pacientes deve-se à ausência da atividade da enzima mitocondrial L-2-hidroxiglutarato desidrogenase ligada ao FAD (L-2-HGDH), devido a mutações no gene L2HGDH, localizado no cromossomo 14q22.1 32,33 . Clinicamente, a L-2-HGA é caracterizada por hipotonia, ataxia progressiva, deficiência mental com graus variados de leucoencefalopatia subcortical e atrofia cerebelar 34 .…”

Section: Acidúria L-2-hidroxiglutáricaunclassified

Acidúrias D-2-hidroxiglutárica e L-2-hidroxiglutárica: uma revisão da literatura

Rodrigues¹,

Vargas²

2016

cbr

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RESUMOAs acidúrias D-2-hidroxiglutárica (D-2-HGA) e L-2-hidroxiglutárica (L-2-HGA) são raras doenças neurometabólicas que constituem um grupo de erros inatos do metabolismo. Essas doenças são causadas pela deficiência das atividades enzimáticas da D-2-hidroxiglutarato desidrogenase na D-2-HGA do tipo I ou isocitrato desidrogenase na D-2-HGA do tipo II, e da L-2-hidroxiglutarato desidrogenase na L-2-HGA. Os principais achados clínicos nos pacientes caracterizam-se por sintomas neurológicos, como convulsões, coma e atrofia cerebral. Também ocorrem lesões cerebrais nos gânglios da base (D-2-HGA, L-2-HGA) e cerebelo (L-2-HGA). Bioquimicamente, essas acidúrias caracterizam-se por acúmulo em tecidos e elevada excreção urinária dos ácidos D-2-hidroxiglutárico (na D-2-HGA) e L-2-hidroxiglutárico (na L-2-HGA). Ainda, uma terceira variante bioquímica da acidúria, a D,L-2-hidroxiglutárica (D,L-2-HGA), é caracterizada por excreção aumentada de ambos enantiômeros do ácido 2-hidroxiglutárico. Em modelo animal, estudos de toxicidade dos ácidos D e L-2-hidroxiglutárico mostraram injúria cerebral, mas não foi elucidado o mecanismo exato causador do dano. Além disso, altos níveis dos ácidos D e L-2-hidroxiglutárico foram encontrados em tumores cerebrais. No entanto, a relação entre a acidúria e o câncer ainda precisa ser esclarecida. Tendo em vista a gravidade da doença, este trabalho teve como objetivo fazer uma revisão bibliográfica acerca do tema, enfatizando as consequências do metabolismo, principalmente para o tecido cerebral, bem como apontar possíveis abordagens terapêuticas. Palavras-chave: ácido D-2-hidroxiglutárico; acidúria D-2-hidroxiglutárica; dano cerebral; ácido L-2-hidroxiglutárico; acidúria L-2-hidroxiglutárica; tumor ABSTRACTThe D-2-hydroxyglutaric (D-2-HGA) and L-2-hydroxyglutaric acidurias (L-2-HGA) are rare neurometabolic diseases that form a group of inborn errors of metabolism. They are caused by a deficiency on the enzyme activities of D-2-hydroxyglutarate dehydrogenase in D-2-HGA type I or isocitrate dehydrogenase in D-2-HGA type II, and L-2-hydroxyglutarate dehydrogenase in L-2-HGA. The main clinical findings in affected patients are related to neurological symptoms, such as convulsions, coma and brain atrophy. Brain injuries also occur in the basal ganglia (D-2-HGA, L-2-HGA) and cerebellum (L-2-HGA). These acidurias are biochemically characterized by the accumulation in tissues and increased urinary excretion of D-2-hydroxyglutaric acid (in D-2-HGA) and L-2-hydroxyglutaric acid (in L-2-HGA). Still, a third biochemical variant of aciduria, called D,L-2-hydroxyglutaric (D,L-2-HGA), is characterized by increased excretion of both enantiomers of 2-hydroxyglutaric acid. In an animal model, toxicity studies on D-and L-2-hydroxyglutaric acids showed brain injury, but the exact mechanism of brain damage was not elucidated. Furthermore, high levels of D-and L-2-hydroxyglutaric acids were found in brain tumors. However, the relationship between cancer and aciduria still needs to be clarified. In view of the seve...

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An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study

Cited by 110 publications

References 41 publications

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Acidúrias D-2-hidroxiglutárica e L-2-hidroxiglutárica: uma revisão da literatura

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