The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3

Williams, Emma; Böckenhauer, Detlef; Hoff, William G. van’t; Johri, Nikhil; Laing, Chris; Sinha, Manish D.; Unwin, Robert J.; Viljoen, Adie; Rumsby, Gill

doi:10.1093/ndt/gfs039

Cited by 62 publications

(83 citation statements)

References 16 publications

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“…The typical presentation is recurrent urolithiasis and marked hypercalciuria in the first decade, but less active stone formation later. 1,2,36,37 HOGA1 encodes the liver-specific mitochondrial enzyme 4-hydroxy-2-oxogluterate aldolase (HOGA), and mutations cause hydroxy-2-oxogluterate aldolase build-up, inhibiting GR/HPR function. 11,38 PH3 accounts for approximately 10% of genetically characterized cases, with some carriers found to be idiopathic stone formers, suggesting sensitivity to haploinsufficiency.…”

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confidence: 99%

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Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

Hopp

Cogal

Bergstralh³

et al. 2015

Journal of the American Society of Nephrology

199

255

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Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.

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confidence: 99%

“…1,39 There are 19 described mutations with c.700+5G.T accounting for about 50% of all HOGA1 alleles; p.E315del is found predominantly in Ashkenazi Jews. 22,36,37,39 No allelic correlations have been established for PH2 or PH3.…”

mentioning

confidence: 99%

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

Hopp

Cogal

Bergstralh³

et al. 2015

Journal of the American Society of Nephrology

199

255

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“…Since the initial report of HOGA1 mutations causing PH3 (Belostotsky et al 2010), several cohorts of patients with persistent hyperoxaluria of unknown aetiology (also referred to as non-type I/type II PH) have been retrospectively studied, and HOGA1 mutations have been identified in~45% of these patients (Beck et al 2013;Monico et al 2011;Williams et al 2012). These findings have significant implications for the way in which patients with hyperoxaluria are investigated and also suggest possible treatments for PH3, now that the gene and enzyme involved have been identified.…”

Section: Discussionmentioning

confidence: 99%

4-Hydroxyglutamate Is a Biomarker for Primary Hyperoxaluria Type 3

et al. 2014

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Primary hyperoxaluria type 3 (PH3) is a recently identified inborn error of 4-hydroxyproline metabolism causing kidney stone disease. Diagnosis to date has relied on mutation detection. The excretion of 4-hydroxyglutamate (4OHGlu) was investigated in controls and a cohort of nine patients with PH3 and their parents using flow injection tandem mass spectrometry. 4OHGlu was stable in acidified urine samples and was not influenced by diet.

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“…It is also characterized by the increase in urinary calcium levels and genetic defects in the HOGA1 gene have also been implicated in cases of idiopathic calcium oxalate urolithiasis [55] . The disease course is more benign compared to other forms and although limited clinical data is available, no cases of ESRD have been reported to date with PH3 [56,57] . Patients with secondary hyperoxaluria have a pre disposition to developing recurrent calcium oxalate stones due to the underlying disorder.…”

Section: Clinical Presentationmentioning

confidence: 98%