An intronic duplication in the alanine: glyoxylate aminotransferase gene facilitates identification of mutations in compound heterozygote patients with primary hyperoxaluria type 1

Purdue, P. Edward; Lumb, M.; Allsop, Jennifer; Danpure, Christopher J.

doi:10.1007/bf00197154

Cited by 55 publications

(30 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to detection of c.33_34insC and other, less frequent changes that are located on exon 1, direct sequencing of this part of the coding region has the advantage of supplying P11L genotyping. Because of the strict association between P11L and IVS1 ϩ 74 bp documented in the past (9,11), the latter change has been used as a marker for the minor AGXT allele. The recent recognition of a breakage in this linkage, documented in an African population (33), underscores that IVS1 ϩ 74 bp may no longer be a suitable surrogate for P11L in certain populations.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive Mutation Screening in 55 Probands with Type 1 Primary Hyperoxaluria Shows Feasibility of a Gene-Based Diagnosis

Monico

Rossetti

Schwanz

et al. 2007

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Mutations in AGXT, a locus mapped to 2q37.3, cause deficiency of liver-specific alanine:glyoxylate aminotransferase (AGT), the metabolic error in type 1 primary hyperoxaluria (PH1). Genetic analysis of 55 unrelated probands with PH1 from the Mayo Clinic Hyperoxaluria Center, to date the largest with availability of complete sequencing across the entire AGXT coding region and documented hepatic AGT deficiency, suggests that a molecular diagnosis (identification of two disease alleles) is feasible in 96% of patients. Unique to this PH1 population was the higher frequency of G170R, the most common AGXT mutation, accounting for 37% of alleles, and detection of a new 3 end deletion (Ex 11_3UTR del). A described frameshift mutation (c.33_34insC) occurred with the next highest frequency (11%), followed by F152I and G156R (frequencies of 6.3 and 4.5%, respectively), both surpassing the frequency (2.7%) of I244T, the previously reported third most common pathogenic change. These sequencing data indicate that AGXT is even more variable than formerly believed, with 28 new variants (21 mutations and seven polymorphisms) detected, with highest frequencies on exons 1, 4, and 7. When limited to these three exons, molecular analysis sensitivity was 77%, compared with 98% for whole-gene sequencing. These are the first data in support of comprehensive AGXT analysis for the diagnosis of PH1, obviating a liver biopsy in most well-characterized patients. Also reported here is previously unavailable evidence for the pathogenic basis of all AGXT missense variants, including evolutionary conservation data in a multisequence alignment and use of a normal control population.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Subsequent to detection of the P11L and I340M polymor-phisms in patients with PH1 and mitochondrial AGT, Purdue et al (9) also identified a closely linked 74-bp duplication in intron 1 (IVS1 ϩ 74 bp). These three polymorphic variants (P11L, I340M, and IVS1 ϩ 74 bp) are now collectively referred to as the "minor" allele of AGXT.…”

mentioning

confidence: 99%

Comprehensive Mutation Screening in 55 Probands with Type 1 Primary Hyperoxaluria Shows Feasibility of a Gene-Based Diagnosis

Monico

Rossetti

Schwanz

et al. 2007

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…The primary, invariant, change in this allele is the presence of the c.32C4T change, which encodes leucine at codon 11 instead of the proline found in the major allele (AGT-Ma) . 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: 99%

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

Acquaviva²,

et al. 2009

View full text Add to dashboard Cite

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.

show abstract

“…Unfortunately, the liver-specific nature of AGT expression in humans precludes a comprehensive analysis of the relationship between the presence of the minor and major AGXT alleles and AGT activity in situ. Although the minor allele contains two amino acid substitutions (P11L and I340M), as well as a 74-base pair duplication in intron 1 (37) and a characteristic VNTR in intron 4 (38), it is only the P11L polymorphism that appears to have any affect on AGT function, including peroxisome-to-mitochondrion mistargeting, inhibition of dimerization, and decreased specific activity. In fact, as far as specific activity is concerned, it appears that the I340M polymorphism is able to, at least partially, normalize some of the consequences of the P11L polymorphism.…”

Section: Situ (Ie In Human Hepatocytes)mentioning

confidence: 99%

Functional Synergism between the Most Common Polymorphism in Human Alanine:Glyoxylate Aminotransferase and Four of the Most Common Disease-causing Mutations

Lumb

Danpure

2000

Journal of Biological Chemistry

130

135

View full text Add to dashboard Cite

The autosomal recessive disorder primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver-specific pyridoxal-phosphate-dependent enzyme alanine:glyoxylate aminotransferase (AGT). Numerous mutations and polymorphisms in the gene encoding AGT have been identified, but in only a few cases has the causal relationship between genotype and phenotype actually been demonstrated. In this study, we have determined the effects of the most common naturally occurring amino acid substitutions (both normal polymorphisms and disease-causing mutations) on the properties, especially specific catalytic activity, of purified recombinant AGT. The results presented in this paper show the following: 1) normal human His-tagged AGT can be expressed at high levels in Escherichia coli and purified in a correctly folded, dimerized and catalytically active state; 2) presence of the common P11L polymorphism decreases the specific activity of purified recombinant AGT by a factor of three; 3) AGTs containing four of the most common PH1-specific mutations (G41R, F152I, G170R, and I244T) are all soluble and catalytically active in the absence of the P11L polymorphism, but in its presence all lead to protein destabilization and aggregation into inclusion bodies; 4) naturally occurring and artificial amino acid substitutions that lead to peroxisome-to-mitochondrion AGT mistargeting in mammalian cells also lead to destabilization and aggregation in E. coli; and 5) the PH1-specific G82E mutation abolishes AGT catalytic activity by interfering with cofactor binding, as does the artificial K209R mutation at the putative site of cofactor Shiff base formation. These results are discussed in the light of the high allelic frequency (ϳ20%) of the P11L polymorphism and its importance in determining the phenotypic manifestations of mutations in PH1.

show abstract

An intronic duplication in the alanine: glyoxylate aminotransferase gene facilitates identification of mutations in compound heterozygote patients with primary hyperoxaluria type 1

Cited by 55 publications

References 6 publications

Comprehensive Mutation Screening in 55 Probands with Type 1 Primary Hyperoxaluria Shows Feasibility of a Gene-Based Diagnosis

Comprehensive Mutation Screening in 55 Probands with Type 1 Primary Hyperoxaluria Shows Feasibility of a Gene-Based Diagnosis

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

Functional Synergism between the Most Common Polymorphism in Human Alanine:Glyoxylate Aminotransferase and Four of the Most Common Disease-causing Mutations

Contact Info

Product

Resources

About