Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease characterized by progressive kidney failure due to renal deposition of calcium oxalate. The disease is caused by a deficiency of alanine:glyoxylate aminotransferase (AGT) which catalyzes the conversion of glyoxylate to glycine. When AGT is absent, glyoxylate is converted to oxalate which forms insoluble calcium salts that accumulate in the kidney and other organs. In the most common phenotype there is a unique phenomenon wherein AGT is mis-targeted to the mitochondria instead of the peroxisomes. The diagnosis of PH1 is complicated by heterogeneity of clinical presentation, course of the disease, biochemical markers, AGT enzymatic activity and genotype. More than 50 mutations and polymorphisms have been reported in the AGT gene; three common mutations accounting for almost 50% of PH1 alleles. The mutations are of all types, with missense making up the largest fraction. There are some mutations with apparent ethnic associations and at least one that appears to be pan-ethnic. Although correlations can in some cases be made between biochemical phenotype and genotype, correlation with clinical phenotype is complicated by the involvement of other genetic and non-genetic factors that affect disease severity. A number of polymorphisms have been described in the AGT gene some of which cause missense changes and, in some cases, alter enzyme activity. As DNA testing becomes more commonly used for diagnosis it is important to correlate observed sequence changes with previously documented changes as an aid to assessing their potential significance.
"The p.S81X mutation is a nonsense mutation that leads to a truncated AGT, and this mutation was speculated to be a pathogenic mutation. p.I202N is another missense mutation and is located on exon 6. Exon 6 spans the PLP co-factor binding site consensus sequence (amino acids 201–221) common to aminotransferases and is critical to the catalytic site
. Crystallisation studies confirmed that the lysine at codon 209 in exon 6 is the actual site of the Schiff base with PLP
[Show abstract][Hide abstract] ABSTRACT: Background
Primary hyperoxaluria type 1 is a rare autosomal recessive disease of glyoxylate metabolism caused by a defect in the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT) that leads to hyperoxaluria, recurrent urolithiasis, and nephrocalcinosis.
Two unrelated patients with recurrent urolithiasis, along with members of their families, exhibited mutations in the AGXT gene by PCR direct sequencing.
Two heterozygous mutations that predict truncated proteins, p.S81X and p.S275delinsRAfs, were identified in one patient. The p.S81X mutation is novel. Two heterozygous missense mutations, p.M1T and p.I202N, were detected in another patient but were not identified in her sibling. These four mutations were confirmed to be of paternal and maternal origin.
These are the first cases of primary hyperoxaluria type 1 to be diagnosed by clinical manifestations and AGXT gene mutations in mainland China. The novel p.S81X and p.I202N mutations detected in our study extend the spectrum of known AGXT gene mutations.
"Diagnosis relies on measurement of 24 hours of urine collection of oxalate, plasma oxalate level, enzymatic assay of AGT catalytic activity from a liver biopsy, and DNA molecular testing of the AGXT gene, which can detect 50%–70% of mutations. Treatment includes: maintenance of high fluid intake; pyridoxine supplements for those who are pyridoxine responsive; and use of potassium or sodium citrate or neutral orthophosphate and magnesium oxide to minimize stone formation.2–5 Little is known about the intrafamilial clinical heterogeneity in PH1. "
[Show abstract][Hide abstract] ABSTRACT: Primary hyperoxaluria type 1 (PH1) is characterized by progressive renal insufficiency culminating in end-stage renal disease, and a wide range of clinical features related to systemic oxalosis in different organs. It is caused by autosomal recessive deficiency of alanine:glyoxylate aminotransferase due to a defect in AGXT gene.
Two brothers (one 6 months old; the other 2 years old) presented with acute renal failure and urinary tract infection respectively. PH1 was confirmed by high urinary oxalate level, demonstration of oxalate crystals in bone biopsy, and pathogenic homozygous known AGXT gene mutation. Despite the same genetic background, same sex, and shared environment, the outcome of the two siblings differs widely. While one of them died earlier with end-stage renal disease and multiorgan failure caused by systemic oxalosis, the older brother is pyridoxine responsive with normal development and renal function.
Clinicians should be aware of extreme intrafamilial variability of PH1 and international registries are needed to characterize the genotype-phenotype correlation in such disorder.
"This microinsertion occurs on major or minor allele of AGXT and it was considered as the most common PH1 mutation on the major allele (31%) . It has been reported that homozygous, would be expected to have no immunoreactive protein and no catalytic activity . In our study, seven of the 8 detected patients were homozygous for the mutation and associated with ESRD. "
[Show abstract][Hide abstract] ABSTRACT: Primary hyperoxaluria type I (PH1) is a rare genetic disorder characterized by allelic and clinical heterogeneity. Four mutations (G170R, 33_34insC, I244T and F152I) account for more than 50% of PH1 alleles and form the basis for diagnostic genetic screening for PH1. We aimed to analyze the prevalence of these specific mutations causing PH1, and to provide an accurate tool for diagnosis of presymptomatic patients as well as for prenatal diagnosis in the affected families.
Polymerase chain reaction/Restriction Fragment Length Polymorphism, were used to detect the four mutations in the AGXT gene in DNA samples from 57 patients belonging to 40 families.
Two mutations causing PH1 were detected in 24 patients (42.1%), with a predominance of the I244T mutation (68% of patients) and 33_34insC (in the remaining 32%). In 92% of cases, mutated alleles were in homozygous state. The presented clinical features were similar for the two mutations. The age of onset was heterogeneous with a higher frequency of the pediatric age. In 58.3% of cases, the presentation corresponded to advanced renal disease which occurred early (< 5 years) in the two mutations. In adolescents, only the I244T mutation was detected (41.1%). I244T and 33_34insC mutations were observed in adult patients, with 17.6% and 12.5% respectively.
Limited mutation analysis can provide a useful first line investigation for PH1. I244T and 33_34insC presented 28.2% of identified mutations causing disease in our cohort. This identification could provide an accurate tool for prenatal diagnosis in the affected families, for genetic counselling and for detection of presymptomatic individuals.
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