Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis

Department of Pediatrics, University of British Columbia - Vancouver, Vancouver, British Columbia, Canada
Molecular Genetics and Metabolism (Impact Factor: 2.83). 09/2004; 83(1-2):38-46. DOI: 10.1016/j.ymgme.2004.08.009
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and Purpose: Kidney stone disease is rare in the South African black (B) population and more prevalent in the white (W) population. Genetic studies have not previously examined this anomaly. The AGT Pro11Leu polymorphism in the alanine:glyoxylate aminotransferase (AGT) enzyme has been suggested as possibly playing a role in the pathogenesis of idiopathic calcium oxalate kidney stones. The present study was undertaken to investigate whether differences occur in the frequency of this polymorphism in subjects of both race groups. Material and Methods: Healthy B (n=60) and W (n=60) male subjects each provided early morning spot urines, blood and buccal cell samples. The AGT Pro11Leu locus was amplified using the Polymerase Chain Reaction and polymorphism was genotyped using a Restriction Fragment Length Polymorphism. Results: There was no difference in the frequency of the AGT Pro11Leu polymorphism, and the major allele (C) was present at a frequency of 0.82 in B and 0.83 in W. Thus the most common genotype (CC) was observed at similar frequencies in both groups (0.68 and 0.65 in B and W respectively), as were the CT and TT genotypes (0.33 & 0.02 and 0.28 & 0.03 in B and W respectively). Neither urinary oxalate nor any other component in the two groups was correlated with the frequency of the AGT Pro11Leu polymorphism. Conclusions: Our data imply that the AGT Pro11Leu polymorphism is not directly responsible for the low incidence of stone formation in B. We conclude that other factors must be instrumental in protecting the B population from urolithiasis.
    Journal of endourology / Endourological Society 12/2013; 28(5). DOI:10.1089/end.2013.0617 · 2.10 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BackgroundPrimary 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.MethodsTwo unrelated patients with recurrent urolithiasis, along with members of their families, exhibited mutations in the AGXT gene by PCR direct sequencing.ResultsTwo 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.ConclusionsThese 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.
    BMC Nephrology 06/2014; 15(1):92. DOI:10.1186/1471-2369-15-92 · 1.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background. Primary hyperoxaluria belongs to a group of rare metabolic disorders with autosomal recessive inheritance. It results from genetic mutations of the AGXT gene, which is more common due to higher consanguinity rates in the developing countries. Clinical features at presentation are heterogeneous even in children from the same family; this study was conducted to determine the clinical characteristics, type of AGXT mutation, and outcome in children diagnosed with PH1 at a tertiary referral center in Oman. Method. Retrospective review of children diagnosed with PH1 at a tertiary hospital in Oman from 2000 to 2013. Result. Total of 18 children were identified. Females composed 61% of the children with median presentation age of 7 months. Severe renal failure was initial presentation in 39% and 22% presented with nephrocalcinosis and/or renal calculi. Family screening diagnosed 39% of patients. Fifty percent of the children underwent hemodialysis. 28% of children underwent organ transplantation. The most common mutation found in Omani children was c.33-34insC mutation in the AGXT gene. Conclusion. Due to consanguinity, PH1 is a common cause of ESRD in Omani children. Genetic testing is recommended to help in family counseling and helps in decreasing the incidence and disease burden; it also could be utilized for premarital screening.
    01/2015; 2015:634175. DOI:10.1155/2015/634175