Mutations in<i>HAO1</i>encoding glycolate oxidase cause isolated glycolic aciduria

Frishberg, Yaacov; Zeharia, Avraham; Lyakhovetsky, Roman; Bargal, Ruth; Belostotsky, Ruth

doi:10.1136/jmedgenet-2014-102529

Cited by 67 publications

(46 citation statements)

References 15 publications

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“…While an enzyme that could catalyze this conversion has not been identified, it is possible that long chain hydroxy-acid oxidase (HAOX2) or an aldehyde oxidase that has some affinity for glycolate could be involved. Two brothers who appear to lack functional glycolate oxidase activity with an elevated urinary glycolate but normal oxalate excretion have recently been identified [25]. This finding warrants investigation due to glycolate oxidase being considered as a target enzyme for lowering endogenous oxalate production [26].…”

Section: Discussionmentioning

confidence: 99%

Hydroxyproline metabolism in a mouse model of Primary Hyperoxaluria Type 3

Knight

Lowther

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Primary Hyperoxaluria Type 3 is a recently discovered form of this autosomal recessive disease that results from mutations in the gene coding for 4-hydroxy-2-oxoglutarate aldolase (HOGA1). This enzyme is one of the 2 unique enzymes in the hydroxyproline catabolism pathway. Affected individuals have increased urinary excretions of oxalate, 4-hydroxy-L-glutamate (4-OH-Glu), 4-hydroxy-2-oxoglutarate (HOG), and 2,4-dihydroxyglutarate (DHG). While HG and HOG are precursor substrates of HOGA1 and increases in their concentrations are expected, how DHG is formed and how HOG is metabolized to DHG and to oxalate are unclear. To resolve these important questions and to provide insight into possible therapeutic avenues for treating this disease, an animal model of the disease would be invaluable. We have developed a mouse model of this disease which has null mutations in the Hoga1 gene and have characterized its phenotype. It shares many characteristics of the human disease, particularly when challenged by the inclusion of hydroxyproline in the diet. An increased oxalate excretion is not observed in the KO mice which may be consistent with the recent recognition that only a small fraction of the individuals with the genotype for HOGA deficiency develop PH.

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Section: Discussionmentioning

confidence: 99%

Hydroxyproline metabolism in a mouse model of Primary Hyperoxaluria Type 3

Knight

Lowther

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Whereas in these patients mild to moderate fibrosis occurs, long term oxaluria however might lead to liver cirrhosis [65]. Deficiency of glycolate oxidase (HAO1), a liver specific enzyme, appears to be asymptomatic in mice [66] and men [67], except for the excretion of glycolate. The HAO1 reaction is considered as a non-essential metabolic pathway [68].…”

Section: Liver Pathology Due To Defects In Other Peroxisomal Pathwaysmentioning

confidence: 98%

Hepatic dysfunction in peroxisomal disorders

Baes

Veldhoven

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders that are either caused by failure to import the enzymes in the organelle or by mutations in the enzymes or in transporters needed to transfer the substrates across the peroxisomal membrane. Hepatic pathology is one of the cardinal features in disorders of peroxisome biogenesis and peroxisomal β-oxidation although it only rarely determines the clinical fate. In mouse models of these diseases liver pathologies also occur, although these are not always concordant with the human phenotype which might be due to differences in diet, expression of enzymes and backup mechanisms. Besides the morphological changes, we overview the impact of peroxisome malfunction on other cellular compartments including mitochondria and the ER. We further focus on the metabolic pathways that are affected such as bile acid formation, and dicarboxylic acid and branched chain fatty acid degradation. It appears that the association between deregulated metabolites and pathological events remains unclear.

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“…This enzyme catalyses the oxidation of glycolate to glyoxylate, the AGT substrate. The absence of GO activity causes isolated glycolic aciduria [28], but it could be hypothesized that hypermorphic genetic HAO1 variants could modulate the enzyme activity leading to a different production of glyoxylate, responsible of the variable phenotype in PH patients.…”

Section: Discussionmentioning

confidence: 99%