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Proposed model of the human mitochondrial hydroxyproline metabolic pathway and the site of action of HOGA. The source of oxalate is still not clear but may arise from degradation of 4-hydroxy-2-oxoglutarate. HO, hydroxyproline oxidase; 1P5CD, 1-pyrroline-5-carboxylate dehydrogenase; AST2, aspartate aminotransferase 2; HOGA, 4-hydroxy-2-oxoglutarate aldolase; AGT2, alanine glyoxylate aminotransferase 2.
Source publication
Mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene have been recently identified in patients with atypical primary hyperoxaluria (PH). However, it was not clearly established whether these mutations caused disease via loss of function or activation of the gene product.
Whole-gene sequencing of HOGA1 was conducted in 28 unrelated patien...
Contexts in source publication
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... the cloning of the HOGA1 gene by Riedel et al. [6], definitive proof that human HOGA catalyses the synthesis of mitochondrial glyoxylate in the pathway of hydroxyproline metabolism has been established. This enzyme catalyses a reversible lyase reaction, whereby 4-hydroxy-2-oxoglutarate is cleaved to glyoxylate and pyruvate ( Figure 1). Since glyoxylate is a known precursor of oxalate, Belostotsky et al. [5] hypothesized that mutations in the gene might lead to activation of the HOGA enzyme increasing the amount of intramitochondrial glyoxylate. ...
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... finding suggests an important role for mitochondrial AGT in glyoxylate detoxification. Since AGT1 is solely perox- isomal in humans, other mechanisms must exist for mito- chondrial glyoxylate detoxification and candidate enzymes include AGT2 and GR (Figure 1). In normal subjects, load- ing doses of gelatine, a collagen source, were shown to produce a slight increase in the output of urine hydroxypro- line and oxalate, but they had a greater effect on glycolate excretion [12]. ...
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... which led to premature termination. The latter of these mutations was also detected in another patient, who was found to be compound heterozygote for this mutation and c.700 + 5G > T. In all cases, urinary oxalate excretion was raised (Table 2), overlapping with that observed in PH1 and PH2. Urinary glycolate was not routinely assayed but was measured in 12 patients and found to be elevated in 5 of them (Table 3) con fi rming that this metabolite should no longer be regarded as being speci fi c for PH1. Urine calcium excretion was determined in 11 patients (Table 3) with levels observed above the reference range in 3 adult patients. None of the paediatric cases were found to have raised urine calcium. The age of disease onset in the PH3 patients was similar to that seen in PH1 and PH2 (Figure 2). Renal stones were the commonest presenting feature in all three forms of PH, with nephrocalcinosis ap- pearing less frequently in PH3 (Table 4). The identi cation of the molecular and biochemical basis of PH Types 1 and 2 has helped to determine the metabolism of glyoxylate. However, there remains a number of patients with unexplained hyperoxaluric stone disease. From the fi ndings presented in this manuscript, we can conclude that in PH3, there is de fi cient rather than over- active function of HOGA as was originally hypothesized [5]. Proof was established by fi nding two nonsense mutations in exon 1. These mutations which cause truncation at amino acid residues 39 and 70 reside close to the mitochondrial cleavage site at the N-terminal of the protein sequence and the resulting peptide would not be catalytically active [6]. We have additionally con fi rmed that the effect of the potential splice site mutation c.700 + 5G > T, previously erroneously reported as c.701 + 4G > T [5], is activation of a cryptic splice site in intron 5 with the introduction of an additional 51 bp of intronic nucleotides into the expressed hepatic messenger RNA. While the liver and kidney are believed to be the prime sites of HOGA1 expression, Monico et al. [7] also showed that a similarly mis-spliced product was obtained in immorta- lized leucocytes. It is not clear from their publication whether this represents ectopic expression following transformation or whether untransformed leucocytes could also be used. The effect of the novel missense mutation, p.Ala36Val, is not easy to con fi rm in the absence of an assay for the enzyme activity. This sequence change has not been described previously as a polymorphic variant and it occurs at the N-terminal of the protein immediately following the cleavage site of the mitochondrial targeting sequence. Both SIFT and Polyphen 2 suggest that the mutation is benign, but it was found in heterozygous form in two separate patients to- gether with another disease causing mutation and with no other sequence changes. In the absence of parental studies, the mutations were assumed to be on separate alleles i.e. in trans. The HOGA enzyme, encoded by the HOGA1 gene, catalyses the last step of the mitochondrial hydroxyproline metabolic pathway. The reaction is fully reversible — a cleavage reaction in which 4-hydroxy-2-oxoglutarate is metabolized to glyoxylate and pyruvate, and a conden- sation reaction in which this reaction is reversed. Thus, glyoxylate is both a substrate and a product of the HOGA enzyme reaction. The equilibrium constants for the forward and reverse reactions, at least for the rat liver enzyme [8, 9], indicate that the former is the favoured reaction. These experiments were carried out in the presence of Tris which strongly binds to glyoxylate and would thus limit its availability as a substrate for the reverse (conden- sation) reaction. It is therefore not clear which reaction would be favoured within the mitochondrial environment. HOGA might have a protective effect metabolizing mitochondrial glyoxylate (analogous to the role of AGT in the peroxisomes and GR in the cytosol). De fi ciency of HOGA could then cause the marked hyperoxaluria observed in PH3 by an accumulation of glyoxylate and metabolism of this substance to oxalate. The alternative is that accumulated 4-hydroxy-2-oxoglutarate, which is known to be relatively unstable [10], is metabolized either enzymatically or non-enzymatically to glyoxylate and/or oxalate. The direction of the HOGA enzyme reaction has signi fi cance for the treatment of PH3 since, if it is a forward (cleavage) reaction, reduction of dietary collagen could potentially reduce the amount of substrate and hence the amount of oxalate produced. In rats, hydroxyproline loading increased the urinary excretion of oxalate, which was signi fi cantly reduced when mitochondrial AGT1 was induced by glucagon [11]. This fi nding suggests an important role for mitochondrial AGT in glyoxylate detoxi fi cation. Since AGT1 is solely peroxisomal in humans, other mechanisms must exist for mitochondrial glyoxylate detoxi fi cation and candidate enzymes include AGT2 and GR (Figure 1). In normal subjects, loading doses of gelatine, a collagen source, were shown to produce a slight in- crease in the output of urine hydroxyproline and oxalate, but they had a greater effect on glycolate excretion [12]. This observation suggests that glycolate, rather than oxalate, is the major metabolite arising from hydroxyproline breakdown in humans and suggests an important role for mitochondrial and/or cytosolic GR in the detoxi fi cation of mitochondrial glyoxylate by its reduction to glycolate. The phenotype of PH3 clearly overlaps that of PH1 and PH2 since the levels of urinary oxalate concentration and the age of onset of the disease are similar (Figure 2). Renal stones were present in all the PH3 patients at presentation, with nephrocalcinosis in only one patient. However, nephrocalcinosis, previously considered to be an uncommon presenting feature of PH2 [13, 14], was present in 46% of PH2 patients diagnosed by the University College London Hospitals laboratory. Urine glycolate was raised in some, but not all, of the PH3 cases we analysed. Thus, urine oxalate and glycolate cannot discrimi- nate reliably among the different types of PH. Increased urinary calcium was not a consistent feature of PH3 in this study, contrasting with previous reports [7, 15], and was only observed in adult patients. In the PH3 patients described previously, 50% presented with stones before 5 years of age [5, 7, 15] an observation consistent with the fi ndings reported here. Of particular note in this manuscript are the three patients who did not present until adulthood, a fi nding which suggests that PH3 may be a milder form of the disease. Audit of our diagnostic database with > 700 patients with clinical symptoms suggestive of PH has shown that PH1 is the most common disorder ( ∼ 63% cases) and that PH2 and PH3 account for ∼ 15 and 9%, respectively. For a diagnostic service, it makes sense to look for PH1 fi rst and then, if AGXT gene sequencing is negative, look for the common mutations causing PH2 and PH3 before going on to sequence the remainder of these genes. The frequency of the recurrent c.700 + 5G > T mutation was 67%, which is substantially higher than the frequency of 24% observed in the cases reported previously [7]. The high frequency of this mutation is such that it could be used as a fi rst-line test for the diagnosis of PH3. This mutation causes the loss of an EcoNI site and could therefore easily be screened for by restriction digest analysis if desired. We now offer a Step 1 test for the diagnosis of PH3 that in- volves sequencing exons 5 and 7 to detect the c.700 + 5G > T mutation as well as the c.944_946delAGG (p. Glu315del) mutation that is prevalent in, but not restricted to, patients of Ashkenazi Jewish descent [5]. In those patients in whom the Step 1 test is negative, the remaining exons of the gene are sequenced in the Step 2 test. Of 28 unrelated patients analysed in our study, only 15 were found to have mutations in the HOGA1 gene, suggesting that there are other as yet undetermined defects in glyoxylate metabolism. Previous studies have already ruled out mutations in the HAO1 [15] and SLC26A6 genes [16]. Other mitochondrial glyoxylate metabolizing enzymes could be implicated in atypical PH and since they will also likely be relevant to the patho- genic mechanisms of PH3, attention should now be fo- cussed on these enzymes and their role in human glyoxylate ...
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... Mutations in the 4-hydroxy-2-oxoglutarate aldolase ( HOGA1 ) gene have been recently identi fi ed in patients with atypical primary hyperoxaluria (PH). However, it was not clearly established whether these mutations caused disease via loss of function or activation of the gene product. Methods. Whole-gene sequencing of HOGA1 was conducted in 28 unrelated patients with a high clinical suspi- cion of PH and in whom Types 1 and 2 had been excluded. Results. Fifteen patients were homozygous or compound heterozygous for mutations in HOGA1 . In total, seven different mutations were identi fi ed including three novel changes: a missense mutation, c.107C > T ( p.Ala36Val), and two nonsense mutations c.117C > A ( p.Tyr39X) and c.208C > T ( p.Arg70X) as well as the previously documented c.860G > T ( p.Gly297Val), c.907C > T ( p.Arg303Cys) and in-frame c.944_946delAGG ( p.Glu315del) mutations. The recurrent c.700 + 5G > T splice site mutation in intron 5 was most common with a frequency of 67%. Expression studies on hepatic messenger RNA demonstrated the pathogenicity of this mutation. Conclusions. The detection of a patient with two novel nonsense mutations within exon 1 of the gene, c.117C > A ( p.Tyr39X) and c.208C > T ( p.Arg70X), provides de fi nitive proof that PH Type 3 is due to de fi ciency of the 4-hydroxy-2-oxoglutarate aldolase enzyme. The primary hyperoxalurias (PHs) are inherited diseases characterized by excessive endogenous formation of oxalate, an end product of metabolism, which is excreted in the urine complexed with calcium. Calcium oxalate is poorly soluble and precipitates out in the urine leading to stones in the renal tract and progressive renal failure. Two forms of PH have been well characterized: PH1 is due to de fi ciency of alanine:glyoxylate aminotransferase (AGT) and PH2 is due to lack of glyoxylate reductase (GR) [1, 2]. There are a number of patients who have the phenotypic and biochemical features of PH but do not have either PH1 or PH2 as the cause of their disease [3, 4]. A third type of disease, PH3, (OMIM 613616) has recently been identi fi ed in some of these unclassi fi ed PH patients by the discovery of mutations in HOGA1 , formerly called DHDPSL [5]. The authors of this paper identi fi ed six mutations: four missense, one in-frame deletion and one splice site mutation. The HOGA1 gene is comprised of seven exons and spans 27 kb of chromosome 10q24 (NCBI reference sequence NG_027922.1). The product of this gene, 4-hydroxy-2-oxoglutarate aldolase (HOGA; E.C. 4.1.3.16), is found predominantly in the liver and kidney [5]. Following the cloning of the HOGA1 gene by Riedel et al. [6], de fi nitive proof that human HOGA catalyses the synthesis of mitochondrial glyoxylate in the pathway of hydroxyproline metabolism has been established. This enzyme catalyses a reversible lyase reaction, whereby 4-hydroxy-2-oxoglutarate is cleaved to glyoxylate and pyruvate (Figure 1). Since glyoxylate is a known precur- sor of oxalate, Belostotsky et al. [5] hypothesized that mutations in the gene might lead to activation of the HOGA enzyme increasing the amount of intramitochon- drial glyoxylate. However, a further 10 patients were recently described [7], including a patient who was compound heterozygote for a stop codon in exon 6 supporting a loss of function disease mechanism in PH3. In this manuscript, we report the fi ndings of DNA sequence analysis of HOGA1 in a cohort of 28 unrelated atypical PH patients from the UK referred to the University College London Hospitals Primary Hyperoxaluria Diagnostic Service. Of the 28 unrelated atypical patients, in whom DNA analysis was conducted, 15 were found to have mutations in HOGA1 . A summary of genotype and the clinical and biochemical characteristics of these PH3 patients are presented in Table 2. The c.700 + 5G > T splice site variant in intron 5 was found in 20 of 30 disease alleles (67% frequency). Eight patients were homozygous for this mutation and four patients were heterozygous. Sequencing of hepatic cDNA from a patient homozygous for the c.700 + 5G > T splice site mutation con fi rmed the pathological nature of this sequence change. The transcript contained 51 nucleotides of intron 5, consistent with activation of a downstream cryptic splice site (HGVS nomenclature, r.[700_701ins700 + 1_700 + 51; 700g > u]). This mutation would result in an in-frame insertion of 17 amino acids between amino acids 234 and 235 of the native protein sequence. All patients with this mutation were Caucasian and this may indicate a founder mutation in northern Europe. The in-frame c.944_946delAGG (p.Glu315del) mutation was detected in a heterozygous state in two patients. Three missense mutations were also found: the previously documented c.860G > T (p.Gly297Val) and c.907C > T (p.Arg303Cys) mutations and a novel c.107C > T (p.Ala36Val) mutation in exon 1. While neither SIFT nor Polyphen 2 prediction programmes indicate that the p.Ala36Val mutation is pathological, this variant, which is at the N-terminal of the protein immediately following the mitochondrial cleavage site, was found in two symptomatic patients (10 and 14, Table 2), in trans with other disease causing mutations. Another patient was a compound heterozygote for two novel nonsense mutations within exon 1: c.117C > A (p.Tyr39X) and c.208C > T (p.Arg70X), which led to premature termination. The latter of these mutations was also detected in another patient, who was found to be compound heterozygote for this mutation and c.700 + 5G > T. In all cases, urinary oxalate excretion was raised (Table 2), overlapping with that observed in PH1 and PH2. Urinary glycolate was not routinely assayed but was measured in 12 patients and found to be elevated in 5 of them (Table 3) con fi rming that this metabolite should no longer be regarded as being speci fi c for PH1. Urine calcium excretion was determined in 11 patients (Table 3) with levels observed above the reference range in 3 adult patients. None of the paediatric cases were found to have raised urine calcium. The age of disease onset in the PH3 patients was similar to that seen in PH1 and PH2 (Figure 2). Renal stones were the commonest presenting feature in all three forms of PH, with nephrocalcinosis ap- pearing less frequently in PH3 (Table 4). The identi cation of the molecular and biochemical basis of PH Types 1 and 2 has helped to determine the metabolism of glyoxylate. However, there remains a number of patients with unexplained hyperoxaluric stone disease. From the fi ndings presented in this manuscript, we can conclude that in PH3, there is de fi cient rather than over- active function of HOGA as was originally hypothesized [5]. Proof was established by fi nding two nonsense mutations in exon 1. These mutations which cause truncation at amino acid residues 39 and 70 reside close to the mitochondrial cleavage site at the N-terminal of the protein sequence and the resulting peptide would not be catalytically active [6]. We have additionally con fi rmed that the effect of the potential splice site mutation c.700 + 5G > T, previously erroneously reported as c.701 + 4G > T [5], is activation of a cryptic splice site in intron 5 with the introduction of an additional 51 bp of intronic nucleotides into the expressed hepatic messenger RNA. While the liver and kidney are believed to be the prime sites of HOGA1 expression, Monico et al. [7] also showed that a similarly mis-spliced product was obtained in immorta- lized leucocytes. It is not clear from their publication whether this represents ectopic expression following transformation or whether untransformed leucocytes could also be used. The effect of the novel missense mutation, p.Ala36Val, is not easy to con fi rm in the absence of an assay for the enzyme activity. This sequence change has not been described previously as a polymorphic variant and it occurs at the N-terminal of ...
Citations
... Specific to PH3, challenges to our understanding include the involvement of HOGA in the catabolism of hydroxyproline, with this enzyme generating glyoxylate rather than detoxifying it. 7,91,92 Moreover, the enzyme exhibits oxaloacetate decarboxylase activity suggesting it may have a wider role in metabolism, 93 whose impact on glyoxylate detoxification and/or oxalate synthesis remains unknown. Hypotheses to explain the mechanism(s) by which oxalate synthesis is increased in PH3 may include the inhibition of GR/HPR by 4-hydroxy-2-oxoglutarate, 9 breakdown of 4hydroxy-2-oxoglutarate to glyoxylate by an alternative aldolase or aldolase(s), 10 and an alteration in cellular redox balance resulting in increased glyoxylate oxidation to oxalate by LDH. ...
Hyperoxaluria is a condition in which there is a pathologic abundance of oxalate in the urine through either hepatic overproduction (primary hyperoxaluria [PH]) or excessive enteric absorption of dietary oxalate (enteric hyperoxaluria [EH]). Severity can vary with the most severe forms causing kidney failure and extrarenal manifestations. To address the current challenges and innovations in hyperoxaluria, the 14th International Hyperoxaluria Workshop convened in Perugia, Italy, bringing together international experts for focused presentation and discussion. The objective of the following report was to disseminate an overview of the proceedings and provide substrate for further thought. The format of this paper follows the format of the meeting, addressing, “PH type 1” (PH1) first, followed by “surgery, genetics, and ethics in PH”, then “PH types 2 and 3,” (PH2 and PH3) and, finally, “EH.” Each session began with presentations of the current clinical challenges, followed by discussion of the latest advances in basic and translational research, and concluded with interactive discussions about prioritizing the future of research in the field to best serve the need of the patients.
... Although some patients exhibit the cardinal clinical manifestations of PH, subsequent genetic screenings fail to uncover suspected genetic causes of the disease. Williams et al. [53] analyzed 28 patients with high suspicion of PH (excluding AGTX and GRHPR mutations), and only 15 patients had HOGA1 gene mutations. Similarly, in the study of Hopp et al. [3] 11.3% of 301 PH families had clinical phenotypes consistent with PH, but no mutations were detected in known genes. ...
Background
Primary hyperoxaluria (PH) is a rare autosomal recessive disorder, mainly due to the increase in endogenous oxalate production, causing a series of clinical features such as kidney stones, nephrocalcinosis, progressive impairment of renal function, and systemic oxalosis. There are three common genetic causes of glycolate metabolism anomalies. Among them, PH type 1 is the most prevalent and severe type, and early end-stage renal failure often occurs.
Summary
This review summarizes PH through pathophysiology, genotype, clinical manifestation, diagnosis, and treatment options. And explore the characteristics of Chinese PH patients.
Key Messages
Diagnosis of this rare disease is based on clinical symptoms, urinary or blood oxalate concentrations, liver biopsy, and genetic testing. Currently, the main treatment is massive hydration, citrate inhibition of crystallization, dialysis, liver and kidney transplantation, and pyridoxine. Recently, RNA interference drugs have also been used. In addition, technologies such as gene editing and autologous liver cell transplantation are also being developed. C.815_816insGA and c.33_34insC mutation in the AGXT gene could be a common variant in Chinese PH1 population. Mutations at the end of exon 6 account for approximately 50% of all Chinese HOGA1 mutations. Currently, the treatment of PH in China still relies mainly on symptomatic and high-throughput dialysis, with poor prognosis (especially for PH1 patients).
... PH2 (OMIM 260000) is caused by the deficit of glyoxylate/hydroxypyruvate reductase (GRHPR), which reduces glyoxylate to glycolate in cytosol and mitochondria, thus preventing its competing oxidation [11][12][13]. PH3 (OMIM 613616) is caused by mutations that functionally inactivate 4-hydroxy-2-oxoglutarate aldolase (HOGA1), which metabolizes 4hydroxy-2-oxoglutarate (HOG) to give glyoxylate and pyruvate [14,15]. ...
Purpose of review
Primary hyperoxalurias (PHs) are rare disorders caused by the deficit of liver enzymes involved in glyoxylate metabolism. Their main hallmark is the increased excretion of oxalate leading to the deposition of calcium oxalate stones in the urinary tract. This review describes the molecular aspects of PHs and their relevance for the clinical management of patients.
Recent findings
Recently, the study of PHs pathogenesis has received great attention. The development of novel in vitro and in vivo models has allowed to elucidate how inherited mutations lead to enzyme deficit, as well as to confirm the pathogenicity of newly-identified mutations. In addition, a better knowledge of the metabolic consequences in disorders of liver glyoxylate detoxification has been crucial to identify the key players in liver oxalate production, thus leading to the identification and validation of new drug targets.
Summary
The research on PHs at basic, translational and clinical level has improved our knowledge on the critical factors that modulate disease severity and the response to the available treatments, leading to the development of new drugs, either in preclinical stage or, very recently, approved for patient treatment.
... HOGA deficiency causes HOG to accumulate in mitochondria and be converted to glyoxylate by different cytoplasmic aldolases. When glyoxylate increases, oxalate production increases as a result of lactate dehydrogenase catalysis [1,2]. PH3 patients will develop urolithiasis early in their life, and kidney stones develop before the age of 5 years in 50% of patients [3][4][5]. ...
... When we categorized PH3 patients into exon 6 skipping homozygotes (c.834G > A/c.834G > A, c.834_834 + 1GG > TT/ c.834_834 + 1GG > TT, or c.834G > A/c.834_834 + 1G G > TT), exon 6 skipping heterozygotes (c.834G > A or c.834_834 + 1GG > TT combined with another mutation) and no exon 6 skipping, we compared the age of onset among the three groups. Patients with the exon 6 skipping homozygotes had the lowest age of onset (0.67 [0.58-1] years), and patients with exon 6 skipping heterozygotes had the highest mean age of onset (1.83 [1][2][3], p = 0.021) ( Table 1, Supplementary Fig. 2). Among 60 PH3 patients, 40 patients' estimated glomerular filtration rate (eGFR) levels were collected, and 22.5% (9/40) of patients presented with decreased eGFR. ...
... The most common missense mutation in Chinese patients was c.769 T > G with an AF of 12.4%. A few nonsense mutations have been reported, including c.85G > T (E29*), c.117C > A (Y39*), c.123delT (V42*), c.208C > T (R70*), c.346C > T (Q116*) and c.763C > T (R255*) [1,7,19,[22][23][24]. Among them, the most common variant was c.208C > T, which was found in four Caucasians and one Chinese patient [1,6,7,15]. ...
Purpose
The aim of our study is to describe the genetic features and correlation between the genotype and phenotype of Chinese patients with primary hyperoxaluria type 3 (PH3).
Methods
The genetic and clinical data of PH3 patients in our cohort were collected and analyzed retrospectively. All published studies of Chinese PH3 populations between January 2010 and November 2022 were searched and enrolled based on inclusive standards.
Results
A total of 60 Chinese PH3 patients (21 cases from our cohort and 39 cases from previous studies) were included. The mean age of onset was 1.62 ± 1.35 (range 0.4–7) years. A total of 29 different variants in the HOGA1 gene were found. The mutations were most commonly clustered in exons 1, 6, and 7. Among the genotypes, exon 6 skipping (c.834G > A and c.834_834 + 1GG > TT mutations) was the most common, followed by c.769 T > G; the allele frequencies (AFs) were 48.76% and 12.40%, respectively. Patients homozygous for exon 6 skipping exhibited a median age of onset of 0.67 (0.58–1) years, which was significantly lower than that observed among heterozygotes and nonexon 6 skipping patients (p = 0.021). A total of 22.5% (9/40) of PH3 patients had a decreased estimated glomerular filtration rate, and one patient with homozygous exon 6 skipping developed end-stage renal disease.
Conclusions
A hotspot mutation, potential hotspot mutation and genotype–phenotype correlation were found in Chinese PH3 patients. This study expands the mutational spectrum and contributes to the understanding of genotypic profiles of PH3, which may provide a potential diagnostic and therapeutic target.
... PH3 results from the deficiency of 4-hydroxy-2oxoglutarate aldolase (HOGA), which is encoded by the HOGA1 gene. It has been considered that PH3 was the least severe form with the maintenance of normal kidney function (Williams et al., 2012). ...
Background: Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to allelic and clinical heterogeneity. This study aimed to analyze the genotype of 21 Chinese patients with primary hyperoxaluria (PH) and explore their correlations between genotype and phenotype.
Methods: Combined with clinical phenotypic and genetic analysis, we identified 21 PH patients from highly suspected Chinese patients. The clinical, biochemical, and genetic data of the 21 patients were subsequently reviewed.
Results: We reported 21 cases of PH in China, including 12 cases of PH1, 3 cases of PH2 and 6 cases of PH3, and identified 2 novel variants (c.632T > G and c.823_824del) in AGXT gene and 2 novel variants (c.258_272del and c.866-34_866-8del) in GRHPR gene, respectively. A possible PH3 hotspot variant c.769T > G was identified for the first time. In addition, patients with PH1 showed higher levels of creatinine and lower eGFR than those with PH2 and PH3. In PH1, patients with severe variants in both alleles had significantly higher creatinine and lower eGFR than other patients. Delayed diagnosis still existed in some late-onset patients. Of all cases, 6 had reached to end-stage kidney disease (ESKD) at diagnosis with systemic oxalosis. Five patients were on dialysis and three had undergone kidney or liver transplants. Notably, four patients showed a favorable therapeutic response to vitamin B6, and c.823_824dup and c.145A > C may be identified as potentially vitamin B6-sensitive genotypes.
Conclusion: In brief, our study identified 4 novel variants and extended the variant spectrum of PH in the Chinese population. The clinical phenotype was characterized by large heterogeneity, which may be determined by genotype and a variety of other factors. We first reported two variants that may be sensitive to vitamin B6 therapy in Chinese population, providing valuable references for clinical treatment. In addition, early screening and prognosis of PH should be given more attention. We propose to establish a large-scale registration system for rare genetic diseases in China and call for more attention on rare kidney genetic diseases.
... In PH3, one common mutation, a single intronic nucleotide change in intron 5, c.700 + 5G > T, leads to missplicing of mRNA and accounts for around 50% of alleles [57,58]. The mutation profile differs in those of Chinese descent where a splice site mutation, c.834_834 + 1GG > TT, accounted for 50% alleles in one series with no c.700 + 5G > T found in this cohort [59]. ...
Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis.
... It is caused by a deficiency of glyoxylate reductase/hydroxypyruvate reductase. [4] 4-hydroxy-2-oxoglutarate aldolase (HOGA1) which encodes the enzyme HOGA is mutated in PH 3. [5] Being least severe, it usually presents in the first decade of life with the less active stone formation and preserved renal function. ...
... Many PH1 patients will have an elevated urinary glycolate; however, this has also been reported in patients with PH3. 97,98 Whilst ESKD in infancy is not uncommon (around 25% of cases), the median age of ESKD is reported at age 10-24 years. 99,100 Genotype-phenotype correlations have been observed with Gly170Arg variants demonstrating a median age of ESKD at 47 years for homozygotes in a western European/North African cohort. ...
RNA interference (RNAi) is a natural biological pathway that inhibits gene expression by targeted degradation or translational inhibition of cytoplasmic mRNA by the RNA induced silencing complex. RNAi has long been exploited in laboratory research to study the biological consequences of the reduced expression of a gene of interest. More recently RNAi has been demonstrated as a therapeutic avenue for rare metabolic diseases. This review presents an overview of the cellular RNAi machinery as well as therapeutic RNAi design and delivery. As a clinical example we present primary hyperoxaluria, an ultrarare inherited disease of increased hepatic oxalate production which leads to recurrent calcium oxalate kidney stones. In the most common form of the disease (Type 1), end‐stage kidney disease occurs in childhood or young adulthood, often necessitating combined kidney and liver transplantation. In this context we discuss nedosiran (Dicerna Pharmaceuticals, Inc.) and lumasiran (Alnylam Pharmaceuticals), which are both novel RNAi therapies for primary hyperoxaluria that selectively reduce hepatic expression of lactate dehydrogenase and glycolate oxidase respectively, reducing hepatic oxalate production and urinary oxalate levels. Finally, we consider future optimizations advances in RNAi therapies.
... Diagnosis was confirmed by genetic analysis in all cases. Six patients were diagnosed by family screening at ages 5 (Table 2 5,6,[9][10][11][20][21][22][23][24][25][26][27][28][29] ). ...
... However, kidney function is not adequately reported in most instances (64% of patients reported in the literature without data) but presumed normal. Between 2010 and 2019, 151 patients were reported (1-38 patients per paper), 5,6,9,10,19,20,[22][23][24][25][26]28,29,[35][36][37][38][39] and a proportion of these patients are included in this paper. Similar to our data, age of diagnosis/disease onset ranged from 1 month to 48 years of life. ...
Outcome data in primary hyperoxaluria type 3 (PH3), described as a less severe form of the PH’s with a low risk of chronic kidney disease, are scarce. To investigate this, we retrospectively analyzed the largest PH3 cohort reported so far. Of 95 patients, 74 were followed over a median of six years. Median age of first symptoms and diagnosis were 1.9 and 6.3 years, respectively. Urolithiasis was the major clinical feature observed in 70% of pediatric and 50% of adult patients. At most recent follow-up available for 56 of the 95 patients, 21.4% were in chronic kidney disease stages 2 or more. For better characterization, samples from 49 patients were analyzed in a single laboratory and compared to data from patients with PH1 and PH2 from the same center. Urinary oxalate excretion was not significantly different from PH1 and PH2 (median: 1.37, 1.40 and 1.16 mmol/1.73m²/24hours for PH1 not responsive to vitamin B6, PH2, and PH3, respectively) but was significantly higher than in vitamin B6 responsive patients with PH1. Urinary oxalate excretion did not correlate to stone production rate nor to estimated glomerular filtration rate. Normocitraturia was present even without alkalinisation treatment; hypercalciuria was found rarely. Median plasma oxalate was significantly different only to the vitamin B6-unresponsive PH1 group. Thus, PH3 is more comparable to PH1 and PH2 than so far inferred from smaller studies. It is the most favorable PH type, but not a benign entity as it constitutes an early onset, recurrent stone disease, and kidney function can be impaired.
... A number of variants are more prevalent in populations like Europeans, Chinese, and Ashkenazi Jews (AJ) [1,5,6]. The two most prevalent pathogenic variants [c.944_946delAGG (p.Glu315del) and c.700+5G>T] with founder effect in different ethnic groups account for about 70% of all the variant alleles [4,5,7,8]. We evaluated whether there are ethnic associations and the presence of founder variants in PH3 variant alleles. ...
Primary hyperoxaluria type-III is a disorder of glyoxylate metabolism, caused by pathogenic variants in the HOGA1 gene. To date more than 50 disease-associated pathogenic sequence variants are identified in the gene. A few of the variants are population specific and are considered to have a founder effect in respective populations. The most prevalent variant, c.700+5G>T, identified frequently in Caucasian (allele frequency 0.63) and European (0.35) populations. Two variants, c.860G>T (p.Gly287Val) and c.944_946delAGG (p.Glu315del), account for 95% of the allele count in patients of Ashkenazi Jews ancestry. A possible mutational hot-spot at c.834 position is frequently found mutated in Chinese patients. This observed ethnic associations of HOGA1 alleles span a spectrum ranging from recurrence limited to an ethnic group to a possible founder-effect.
