Primary hyperoxaluria type 1: Genotypic and phenotypic heterogeneity

Danpure, Christopher J.; Jennings, Patricia R.; Fryer, P.; Purdue, P. Edward; Allsop, Jennifer

doi:10.1007/bf00711363

Cited by 106 publications

(77 citation statements)

References 27 publications

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“…PH was diagnosed in seven patients during the first half of the Introduction Primary hyperoxaluria (PH), particularly its most common form, type 1, is characterized by increased production of oxalic acid, resulting in recurrent urolithiasis and nephrocalcinosis which often progresses to end-stage renal failure (ESRF) and generalized oxalosis [1,2]. The clinical spectrum of PH is very large and patients are seen at all ages.…”

Section: Resultsmentioning

confidence: 99%

“…The clinical heterogeneity is not sufficiently explained by remaining activity of the peroxisomal enzyme AGT or by mitochondrial mistargeting; other factors (e.g. episodes of dehydration) are important as well [ 1 ]. Initial symptoms may be very vague (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Much progress has been made unravelling the molecular basis of PH type 1 [1], but clinical assessment still runs far behind. Normal urinary oxalate/ creatinine ratios for different age groups are available for screening purposes [3,8].…”

Section: Discussionmentioning

confidence: 99%

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Changing pattern of primary hyperoxaluria in Switzerland

Kopp

Leumann

1995

Nephrology Dialysis Transplantation

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Background. The clinical course of primary hyperoxaluria (PH) is greatly variable and diagnosis is often delayed. Little is known about the overall occurrence and current prognosis. Methods. We evaluated all known patients with PH residing and observed in Switzerland during the last 15 years with the help of a survey among Swiss nephrologists. Results. Of the 25 patients observed between 7/79 and 6/94 in Switzerland, 18 were alive in 1994-14 on conservative therapy and four on renal replacement therapy (RRT). Twenty-two patients had PH type 1; the exact type was not determined in three. The estimated prevalence of PH (type 1) is 2 per million population; the minimal incidence is 1 per 100000 live births. Diagnosis was delayed by 8 years (median) except in infants. Five patients were pyridoxine sensitive. According to life table analysis, 20% of patients were in end-stage renal failure (ESRF) and 10% had died by the age of 15 years, and 50% were in ESRF and 20% dead at 25 years. Prognosis has improved: Five of 13 patients died during the first half of the observation period as opposed to two of 20 in the second part. Conclusions. Overall prognosis appears better than hitherto believed considering the large clinical spectrum of PH. Greater awareness of PH is needed to improve further long-term prognosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Changing pattern of primary hyperoxaluria in Switzerland

Kopp

Leumann

1995

Nephrology Dialysis Transplantation

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“…A complicating factor with AGT, but as far as we are aware no other peroxisomal protein, is that its intracellular compartmentalization varies between different mammalian species (25)(26)(27)(28)(29)(30). For example, in the human, rabbit, and guinea pig hepatocytes, AGT is peroxisomal.…”

mentioning

confidence: 99%

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Huber

Birdsey

Lumb

et al. 2005

Journal of Biological Chemistry

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Although human alanine:glyoxylate aminotransferase (AGT) is imported into peroxisomes by a Pex5p-dependent pathway, the properties of its C-terminal tripeptide (KKL) are unlike those of any other type 1 peroxisomal targeting sequence (PTS1). We have previously suggested that AGT might possess ancillary targeting information that enables its unusual PTS1 to work. In this study, we have attempted to locate this information and to determine whether or not it is a characteristic of all vertebrate AGTs. Using the two-hybrid system, we show that human AGT interacts with human Pex5p in mammalian cells, but not yeast cells. Using (immuno)fluorescence microscopic analysis of the distribution of various constructs expressed in COS cells, we show the following. 1) The putative ancillary peroxisomal targeting information (PTS1A) in human AGT is located entirely within the smaller C-terminal structural domain of 110 amino acids, with the sequence between Val-324 and Ile-345 being the most likely candidate region. 2) The PTS1A is present in all mammalian AGTs studied (human, rat, guinea pig, rabbit, and cat), but not amphibian AGT (Xenopus). 3) The PTS1A is necessary for peroxisomal import of human, rabbit, and cat AGTs, but not rat and guinea pig AGTs. We speculate that the internal PTS1A of human AGT works in concert with the C-terminal PTS1 by interacting with Pex5p indirectly with the aid of a yet-to-be-identified mammal-specific adaptor molecule. This interaction might reshape the tetratricopeptide repeat domain allosterically, enabling it to accept KKL as a functional PTS1.Alanine:glyoxylate aminotransferase (AGT, 1 EC 2.6.1.44) catalyzes the transamination of the intermediary metabolite glyoxylate to glycine. A deficiency of AGT, as occurs in the hereditary disease primary hyperoxaluria type 1, allows glyoxylate to be oxidized to oxalate instead. The resulting increased synthesis and excretion of oxalate leads to the deposition of insoluble calcium oxalate in the kidney and urinary tract and, ultimately, renal failure (1). AGT is normally peroxisomal in human liver, but in a subset of primary hyperoxaluria type 1 patients it is mistargeted to mitochondria (2). Although the molecular basis of the peroxisome-to-mitochondrion mistargeting of AGT in primary hyperoxaluria type 1 has been subjected to extensive investigation (3-6), its normal targeting to peroxisomes has received much less attention (7,8).Peroxisomal import of human AGT is dependent on the presence of the type 1 peroxisomal targeting sequence (PTS1) receptor Pex5p, but not the PTS2 receptor Pex7p (7). However, several features of the peroxisomal targeting of AGT are unusual when compared with the targeting of other peroxisomal proteins. The C-terminal tripeptide of human AGT is KKL (9), which has a two-out-of-three match with the prototypical consensus PTS1 of (S/A/C)(K/R/H)(L/M) (10, 11). KKL is necessary for peroxisomal targeting of human AGT but insufficient to direct the peroxisomal targeting of reporter proteins, such as bacterial chloramphenicol acetyl...

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“…Numerous intragenic polymorphisms have also been identified, the most common being P11L and I340M replacements, which co-segregate with allelic frequencies of 20% in normal European and North American populations and 50% in PH1 patients (5,8). The combined presence of the P11L and I340M polymorphisms defines the minor AGXT allele, whereas their absence defines the major allele (9).…”

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

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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.

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Primary hyperoxaluria type 1: Genotypic and phenotypic heterogeneity

Cited by 106 publications

References 27 publications

Changing pattern of primary hyperoxaluria in Switzerland

Changing pattern of primary hyperoxaluria in Switzerland

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

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

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