<i>HOGA1</i> Gene Mutations of Primary Hyperoxaluria Type 3 in Tunisian Patients

M'dimegh, Saoussen; Aquaviva-bourdain, Cécile; Omezzine, Asma; Souche, Geneviéve; M'barek, Ibtihel; Abidi, Kamel; Gargah, Tahar; Abroug, S.; Bouslama, Ali

doi:10.1002/jcla.22053

Cited by 13 publications

(20 citation statements)

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“…For PH‐II, which accounts for 10% of the PH patients and around 20% of the patients developing ESKD, kidney alone transplantation has been a recommended therapy. Whereas, PH‐III is a relatively mild disorder with a few cases with CKD and ESKD 13,25,26 . Therefore, early diagnosis of PH is crucial, and it currently relies on genetic testing largely because liver biopsy is an invasive and expensive method for the diagnosis 27 …”

Section: Discussionmentioning

confidence: 99%

“…The phenotypic statuses of heterozygous variants in the AGXT and GRHPR genes have not been described yet. However, HOGA1 heterozygosity for some variants in association with milder hyperoxaluria or idiopathic urinary stone disease has been reported 12,26 . The observed phenotypes in heterozygous individuals in PH‐I and II may be modulated by mutations in some other yet uncharacterized genes affecting glyoxylate metabolism or this may be due to various potential environmental factors.…”

Section: Discussionmentioning

confidence: 99%

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Primary hyperoxaluria: Comprehensive mutation screening of the disease causing genes and spectrum of disease‐associated pathogenic variants

et al. 2022

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The primary hyperoxalurias are rare disorders of glyoxylate metabolism. Accurate diagnosis is essential for therapeutic and management strategies. We conducted a molecular study on patients suffering from recurrent calcium‐oxalate stones and nephrocalcinosis and screened primary hyperoxaluria causing genes in a large cohort of early‐onset cases. Disease‐associated pathogenic‐variants were defined as missense, nonsense, frameshift‐indels, and splice‐site variants with a reported minor allele frequency <1% in controls. We found pathogenic‐variants in 34% of the cases. Variants in the AGXT gene causing PH‐I were identified in 81% of the mutation positive cases. PH‐II‐associated variants in the GRHPR gene are found in 15% of the pediatric PH‐positive population. Only 3% of the PH‐positive cases have pathogenic‐variants in the HOGA1 gene, responsible to cause PH‐III. A population‐specific AGXT gene variant c.1049G>A; p.Gly350Asp accounts for 22% of the PH‐I‐positive patients. Pathogenicity of the identified variants was evaluated by in‐silico tools and ACMG guidelines. We have devised a rapid and low‐cost approach for the screening of PH by using targeted‐NGS highlighting the importance of an accurate and cost‐effective screening platform. This is the largest study in Pakistani pediatric patients from South‐Asian region that also expands the mutation spectrum of the three known genes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Primary hyperoxaluria: Comprehensive mutation screening of the disease causing genes and spectrum of disease‐associated pathogenic variants

et al. 2022

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“…PH3 involves functional loss of the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) enzyme in mitochondria encoded by the HOGA1 gene (Figure ). , Mutations in the HOGA1 gene (also called DHDPSL gene) are responsible for PH3 and have been associated with PH3 patients in different populations. , The exact mechanism by which genetic mutations in the HOGA1 gene contribute to downstream oxalate accumulation is unclear. PH3 likely exists in the first months to years of life with early symptomatic nephrolithiasis .…”

Section: Pathology and Genetics Of Phmentioning

confidence: 99%

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies

Liu

Zhao

Shah

et al. 2022

ACS Pharmacol. Transl. Sci.

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Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.

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“…It can be defined as the elevated urinary oxalate-to-creatinine ratio of 0.5-1.0 mmol/1.73 m 2 per day and may be presented with elevated urinary calcium excretion (>4 mg/kg body weight per day; Hoppe, 2012). The majority of the affected individuals reported had preserved renal function, with a few cases recently showing a decline in renal function and progression to ESKD (Allard et al, 2015;M'dimegh et al, 2017;Richard et al, 2017).…”

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confidence: 99%

“…A number of reports have identified HOGA1 gene variants that are associated with a range of associated phenotypes from a mild to severe disease (Allard et al, 2015;Belostotsky et al, 2010;M'dimegh et al, 2017;Monico et al, 2011;Richard et al, 2017; X. Wang et al, 2015;Y.…”

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confidence: 99%

HOGA1 gene pathogenic variants in primary hyperoxaluria type III: Spectrum of pathogenic sequence variants, and phenotypic association

et al. 2022

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Primary hyperoxalurias (PH) are a group of rare heterogeneous disorders characterized by deficiencies in glyoxylate metabolism. To date, three genes have been identified to cause three types of PH (I, II, and III). The HOGA1 gene caused type III in around 10% of the PH cases. Disease-associated pathogenic variants have been reported from several populations and a comprehensive spectrum of these mutations and genotype-phenotype correlation has never been presented. In this study, we describe new cases of the HOGA1 gene pathogenic variants identified in our population. We report the first case of ESKD with successful kidney transplantation with 5 years of follow-up. Furthermore, a comprehensive overview of PH type III associated HOGA1 gene variants was carried out. Compiling the data from the literature, we reviewed 57 distinct HOGA1 gene pathogenic variants in 175 patients worldwide. The majority of reported variants are missense variants that predicted a loss of function mechanism as the underlying pathology. There has been evidence of the presence of founder mutations in several populations like Europeans, Ashkenazi Jews, Arab, and Chinese populations. No significant genotype-phenotype correlation was identified concerning the ages of onset of the disease and biochemical and metabolic parameters. Nephrocalcinosis was rare in patients with disease-associated variants. Most of the patients were presented with urolithiasis early in life; only five cases reported disease progression after the second decade of life. The establishment of impairment of renal function in 8% of all the reported cases makes this type a relatively severe form of primary hyperoxaluria, not a benign etiology as suggested previously.

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HOGA1 Gene Mutations of Primary Hyperoxaluria Type 3 in Tunisian Patients

Abstract: This study expanded the number of PH3 patients from 63 to 66 cases. The p.Pro190Leu and the p.Gly287Val mutations found in this study can provide a first-line investigation in Tunisian PH1 patients.

Cited by 13 publications

References 17 publications

Primary hyperoxaluria: Comprehensive mutation screening of the disease causing genes and spectrum of disease‐associated pathogenic variants

Primary hyperoxaluria: Comprehensive mutation screening of the disease causing genes and spectrum of disease‐associated pathogenic variants

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies

HOGA1 gene pathogenic variants in primary hyperoxaluria type III: Spectrum of pathogenic sequence variants, and phenotypic association

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