Selected Exonic Sequencing of the AGXT Gene Provides a Genetic Diagnosis in 50% of Patients with Primary Hyperoxaluria Type 1

Williams, Emma; Rumsby, Gill

doi:10.1373/clinchem.2006.084434

Cited by 63 publications

(54 citation statements)

References 22 publications

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“…Additional sequence changes on the minor allele are the presence of a 74-bp imperfect duplication in intron 1 containing the two further substitutions c.166-100A4C and c.166-96T4A [Purdue et al, 1991a], a variable number of tandem repeats (VNTR) in intron 4 [Danpure et al, 1994b], and several other single nucleotide changes-c.165116A4G (Williams and Rumsby; Waterham; this work Ã ), c.264C4T [Danpure et al, 1994a], c.358113C4T ], and another missense change, p.Ile340Met (c.1020A4G) in exon 10 . The catalytic activity of the minor allele is significantly less than that of the major, ranging from $50 to 64% [Lumb and Danpure, 2000;Williams and Rumsby, 2007], with the difference entirely attributable to the leucine at codon 11 [Lumb and Danpure, 2000].…”

Section: Polymorphismsmentioning

confidence: 94%

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Primary hyperoxaluria type 1: update and additional mutation analysis of theAGXTgene

Acquaviva²,

et al. 2009

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Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, inherited disorder of glyoxylate metabolism arising from a deficiency of the alanine: glyoxylate aminotransferase (AGT) enzyme, encoded by the AGXT gene. The disease is manifested by excessive endogenous oxalate production, which leads to impaired renal function and associated morbidity. At least 146 mutations have now been described, 50 of which are newly reported here. The mutations, which occur along the length of the AGXT gene, are predominantly singlenucleotide substitutions (75%), 73 are missense, 19 nonsense, and 18 splice mutations; but 36 major and minor deletions and insertions are also included. There is little association of mutation with ethnicity, the most obvious exception being the p.Ile244Thr mutation, which appears to have North African/Spanish origins. A common, polymorphic variant encoding leucine at codon 11, the so-called minor allele, has significantly lower catalytic activity in vitro, and has a higher frequency in PH1 compared to the rest of the population. This polymorphism influences enzyme targeting in the presence of the most common Gly170Arg mutation and potentiates the effect of several other pathological sequence variants. This review discusses the spectrum of AGXT mutations and polymorphisms, their clinical significance, and their diagnostic relevance.

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Section: Polymorphismsmentioning

confidence: 94%

“…Excessive oxalate excretion is an indicator of this disease, although the test is not specific for PH1 and may actually be misleadingly reduced in renal failure. Thus more sophisticated tests, including genetic analysis Williams and Rumsby, 2007] and/or enzymology [Allsop et al, 1987;Rumsby et al, 1997], are required to make a diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Primary hyperoxaluria type 1: update and additional mutation analysis of theAGXTgene

Acquaviva²,

et al. 2009

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“…The results from the yeast assays are generally consistent with the reported activities. One exception to this was the reported in vitro activity for AGTma-R233C, which was found to show greatly reduced catalytic activity (14% of wild type) when expressed in bacteria (20). The mutation R233C causes disease when combined with the minor allele mutations P11L and I340M but is not disease-causing in the major allele background.…”

Section: Expression Of Agt Disease Variants In Yeast-yeast Alaninementioning

confidence: 95%

In Vivo and in Vitro Examination of Stability of Primary Hyperoxaluria-associated Human Alanine:Glyoxylate Aminotransferase

Hopper

Pittman

Fitzgerald

et al. 2008

Journal of Biological Chemistry

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Primary hyperoxaluria type I is a severe kidney stone disease caused by mutations in the protein alanine:glyoxylate aminotransferase (AGT). Many patients have mutations in AGT that are not deleterious alone but act synergistically with a common minor allele polymorphic variant to impair protein folding, dimerization, or localization. Although studies suggest that the minor allele variant itself is destabilized, no direct stability studies have been carried out. In this report, we analyze AGT function and stability using three approaches. First, we describe a yeast complementation growth assay for AGT, in which we show that human AGT can substitute for function of yeast Agx1 and that mutations associated with disease in humans show reduced growth in yeast. The reduced growth of minor allele mutants reflects reduced protein levels, indicating that these proteins are less stable than wild-type AGT in yeast. We further examine stability of AGT alleles in vitro using two direct methods, a mass spectrometry-based technique (stability of unpurified proteins from rates of H/D exchange) and differential scanning fluorimetry. We also examine the effect of known ligands pyridoxal 5-phosphate and aminooxyacetic acid on stability. Our work establishes that the minor allele is destabilized and that pyridoxal 5-phosphate and aminooxyacetic acid binding significantly stabilizes both alleles. To our knowledge, this is the first work that directly measures relative stabilities of AGT variants and ligand complexes. Because previous studies suggest that stabilizing compounds (i.e. pharmacological chaperones) may be effective for treatment of primary hyperoxaluria, we propose that the methods described here can be used in high throughput screens for compounds that stabilize AGT mutants.Deficiencies in the enzyme alanine:glyoxylate aminotransferase (AGT) 3 cause primary hyperoxaluria type I (PH1), a severe autosomal recessive kidney stone disease (1, 2). In humans, AGT is responsible for conversion of glyoxylate to glycine in the liver. Without functional AGT, glyoxylate builds up and is converted to calcium oxalate, which is deposited in the kidneys and can lead to kidney stones and renal failure. In many patients, deficiency of AGT results from one or two amino acid changes that decrease the stability of this enzyme. As a result, AGT may be degraded, become improperly localized, or form nonfunctional aggregates (1, 2).Over 50 different mutations of AGT and two polymorphic variants have been identified (1, 3). The two allelic forms consist of a "wild-type" major allele, AGTma, and a minor allele, AGTmi. The minor allele is present in ϳ20% of European and North American populations and contains P11L and I340M substitutions in the amino acid sequence and a 74-bp duplication in intron 1 (4, 5). The P11L and I340M substitutions, particularly P11L, have several biochemical effects, including decreasing catalytic activity and slowing the dimerization rate, but by themselves are not disease-causing (4, 5). The minor allele of AGT is delete...

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“…There are 150 known mutations for AGXT [67] , 16 for GRHP [26] and 15 for HOGA1 [28,5557,68] . Williams et al [69] showed that targeted analysis of the three most common mutations in AGXT (c.33_34insC, c.508G>A, and c.731T>C) provides the diagnosis in 34.5% PH1 patients while exon sequencing of exon 1, 4 and 7 increases the yield and allows diagnosis in 50% PH1 patients. Prenatal diagnosis can be done by testing chorionic villi.…”

Section: Systemic Oxalosismentioning

confidence: 99%

Primary and secondary hyperoxaluria: Understanding the enigma

Bhasin

Ürekli

Atta

2015

WJN

151

125

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Selected Exonic Sequencing of the AGXT Gene Provides a Genetic Diagnosis in 50% of Patients with Primary Hyperoxaluria Type 1

Cited by 63 publications

References 22 publications

Primary hyperoxaluria type 1: update and additional mutation analysis of theAGXTgene

Primary hyperoxaluria type 1: update and additional mutation analysis of theAGXTgene

In Vivo and in Vitro Examination of Stability of Primary Hyperoxaluria-associated Human Alanine:Glyoxylate Aminotransferase

Primary and secondary hyperoxaluria: Understanding the enigma

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