Biochemical and cellular effects of a novel missense mutation of the AGXT gene associated with Primary Hyperoxaluria Type 1

Gatticchi, Leonardo; Dindo, Mirco; Pampalone, Gioena; Conter, Carolina; Cellini, Barbara; Takayama, Tatsuya

doi:10.1016/j.bbrc.2023.01.042

Cited by 2 publications

(4 citation statements)

References 30 publications

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“…The speci c activity of AGT is reduced by most of the pathogenic mutations. The factors caused by these mutations include defects in the catalytic activity of the enzyme, reduction in intracellular stability, not proper folding, mistargeting to mitochondria, aggregation, and/or dimerization [15].…”

Section: Discussionmentioning

confidence: 99%

“…The ndings of Boussetta and companions revealed that the p.Gly190Arg mutation was the second most common mutation withan allele frequency, of 17.4 [14].The other most common mutations within the PH1 category identi ed in a study by Hashmi and colleagues were Gly350Asp and Gly82Glu [9]. In another mutational analysis study by Abid and colleagues, c.1049G > A; p.Gly350Asp genetic mutation was found in 22% of the patients with PH1 [11].Other mutational studies include c.1093G > T(p.Gly365Cys) mutation identi ed in a Japanese patient [15];the c.…”

Section: Mutational Analysis Of the Agxt Gene Causing Ph1 Across Globementioning

confidence: 99%

“…Primary Hyperoxaluria Type1 (PH1, OMIM: 259900), a rare metabolic disorder of glyoxylate [4], is caused by a functional defect in the alanine glyoxylate aminotransferase (AGT) enzyme. This de ciency in the AGT enzyme is because of a mutation in the AGXT gene [15]. In hepatocytes' peroxisomes,aninsu cient amount of AGT disrupts the metabolism of glyoxylate leading to over production of oxalate which is excreted through urination [19].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Analysis of the AGXT Gene Detected a Missense and Pathogenic Variant Associated with Primary Hyperoxaluria Type 1; a Case Study

saba,

Khan,

Rehman

et al. 2023

Preprint

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Background Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive genetic disorder triggered by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene. Early detection of PH1 is a pre-requisite as it causes End Stage Renal Disease (ESRD) in most patients in the early stages. An eleven years old girl with a history of kidney disease and stones and with phenotypic characteristics of PH1 was brought to the laboratory. A c.568G>A mutation in AGXT gene, which is responsible for PH1, is found in a homozygous condition. Further study revealed the detection of the mutation in heterozygous form in both the parents. This study provides insight to generate more reliable genetic markers for the early detection of PH1 in a family or a population. This can lead to better and earlier treatment strategies. Case Presentation This study aimed to detect the AGXT gene mutationswhich are responsible for primary hyperoxaluriain the patient.AGXT gene screening was done in her parents for identifying the root cause and zygosity of the mutation. The AGXT gene on chromosome2q37.3was amplified via polymerase chain reaction and sequenced by Sanger sequencing. Molecular modeling and genetic change analysis was performed by using in-silico parameters. Conclusion The sequence analysis revealed the presence of a missense and pathogenic variant in the homozygous condition in the AGXT gene exon 5;c.568G>A with protein change p. Gly190Arg in the patient. Parental screening showed that the patient received one allele from her father and the other from her mother. A liver transplant followed by a kidney transplant was carried out in the patient with 6 months difference. The study emphasized that as theb mutation p.Gly190Arg is reported as a cause of PH1, this mutation can be considered an early diagnostic marker for PH1.

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Section: Discussionmentioning

confidence: 99%

Section: Mutational Analysis Of the Agxt Gene Causing Ph1 Across Globementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Analysis of the AGXT Gene Detected a Missense and Pathogenic Variant Associated with Primary Hyperoxaluria Type 1; a Case Study

saba,

Khan,

Rehman

et al. 2023

Preprint

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“…As for PH1, our group recently setup a new cellular model of disease based on HepG2 cells, a cell line of hepatic origin showing a conserved glyoxylate/oxalate metabolism [ 58 , 59 ]. The model was used to support diagnosis in a PH1 patient who was compound heterozygous for a validated pathogenic mutation and a novel mutation, p.Gly365Cys [ 60 ▪ ]. Through functional studies at protein and cellular level, we confirmed the pathogenicity of the Gly365 mutation by showing that it induces a conformational change that compromises PLP binding, in turn causing a catalytic impairment and a reduced intracellular stability of AGT.…”

Section: Molecular Pathogenesis Of Primary Hyperoxaluria Type 1 (Ph1)mentioning

confidence: 99%

A molecular journey on the pathogenesis of primary hyperoxaluria

Cellini

2024

Current Opinion in Nephrology &Amp; Hypertension

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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.

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Biochemical and cellular effects of a novel missense mutation of the AGXT gene associated with Primary Hyperoxaluria Type 1

Cited by 2 publications

References 30 publications

Molecular Analysis of the AGXT Gene Detected a Missense and Pathogenic Variant Associated with Primary Hyperoxaluria Type 1; a Case Study

Molecular Analysis of the AGXT Gene Detected a Missense and Pathogenic Variant Associated with Primary Hyperoxaluria Type 1; a Case Study

A molecular journey on the pathogenesis of primary hyperoxaluria

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