Two Novel AGXT Mutations Cause the Infantile Form of Primary Hyperoxaluria Type I in a Chinese Family: Research on Missed Mutation

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder characterized by a defect in the liver-specific peroxisomal enzyme alanine-glyoxylate and serine-pyruvate aminotransferase (AGT). This disorder results in hyperoxaluria, recurrent urolithiasis, and nephrocalcinosis. Three forms of PH1 have been reported. Data on the infantile form of PH1 are currently limited in literature. Despite the fact that China is the most populated country in the world, only a few AGXT mutations have been reported in several Chinese PH1 patients. In the present study, we investigated a Chinese family in which two siblings are affected by the infantile form of PH1. Sanger sequencing was carried out on the proband, but the results were misleading. Two novel missense mutations (c.517T > C/p.Cys173Arg and c.667A > C/p.Ser223Arg) of the AGXT gene were successfully detected through whole-exome sequencing. These two mutations occurred in the highly conserved residues of the AGT. Four software programs predicted both mutations as the cause of the disease. A postmortem examination was performed and revealed the occurrence of global nephrocalcinosis on both kidneys. The crystals were collected and analyzed as calcium oxalate monohydrate. This study extends the knowledge on the clinical phenotype–genotype correlation of the AGXT mutation. That is, (i) two novel missense mutations were identified for the infantile form of PH1 and (ii) the same AGXT genotype caused the same infantile form of PH1 within the family.

Deleterious AGXT Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep

“…Further literature search revealed that a pathogenic missense variant with the same amino acid exchange in humans (p.Cys173Tyr, rs180177231) was associated with severely decreased catalytic activity and negative immunoreactivity in vitro and was found heterozygous in one PH1 patient [ 19 ]. Recently, another variant at the same position (p.Cys173Arg) was described in two closely related human PH1 patients exhibiting compound heterozygosity [ 20 ].…”

“…This amino acid exchange affects a residue highly conserved across multiple species and the ovine position Cys195 corresponds to amino acid position Cys173 of human AGXT protein. Several mutations affecting this residue have been previously reported in humans affected by PH1 [ 18 , 20 , 24 ]. Most recently, two missense heterozygous variants (AGXT: p.Cys173Arg; p.Ser223Arg) were identified in two patients from one family [ 20 ].…”

“…Several mutations affecting this residue have been previously reported in humans affected by PH1 [ 18 , 20 , 24 ]. Most recently, two missense heterozygous variants (AGXT: p.Cys173Arg; p.Ser223Arg) were identified in two patients from one family [ 20 ]. Interestingly, while the two probands suffering from a severe infantile form of PH1 carried both variants, all four heterozygous carriers of only the p.Cys173Arg variant were affected by kidney stones.…”

“…Interestingly, while the two probands suffering from a severe infantile form of PH1 carried both variants, all four heterozygous carriers of only the p.Cys173Arg variant were affected by kidney stones. On the other hand, five heterozygous carriers of only the p.Ser223Arg variant showed no signs of disease [ 20 ]. Furthermore, a pathogenic p.Cys173Tyr variant showed severely decreased catalytic activity and negative immunoreactivity in vitro [ 19 ].…”

Genetic risk scores to predict the prognosis of chronic heart failure patients in Chinese Han

“…Seven genes were used for GRS construction: Alanine–glyoxylate and serine–pyruvate aminotransferase (AGXT), Solute carrier family 25 member 13 (SLC25A13), Histidine‐rich glycoprotein (HRG), Apolipoprotein B (ApoB), SOD3, Synemin (SYNM) and TLN2. AGXT are mostly localized in the peroxisomes, and may be associated with primary hyperoxaluria type 1 . SLC25A13 encodes aspartate/glutamate carrier isoform 2 (AGC2) and involves in numerous metabolic pathways including energy metabolism pathway and cell functions .…”