Mutational Basis of Adenine Phosphoribosyltransferase Deficiency

Sahota, Amrik; Chen, Ju; Stambrook, Peter J.; Tischfield, Jay A.

doi:10.1007/978-1-4615-7703-4_16

Cited by 26 publications

(12 citation statements)

References 4 publications

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“…All probands carrying at least one IVS4+2insT mutation originated from France or other European countries, whereas IVS4+2insT was not detected in five families from other ethnic groups (6). The IVS4 +2insT mutation had been identified previously in several families from Europe and seems to be the most common cause of APRT deficiency in this population (10,19,24,27,28). Another common mutation is a missense (Asp65Val) found in British, Icelandic, and Spanish patients (6,20,27).…”

Section: Geneticsmentioning

confidence: 77%

Adenine Phosphoribosyltransferase Deficiency

Bollée

Harambat

Bensman

et al. 2012

Clinical Journal of the American Society of Nephrology

105

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SummaryComplete adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation of this compound and the formation of urinary crystals and stones. The disease can present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available-including stone analysis, crystalluria, and APRT activity measurement-make the diagnosis easy to confirm when APRT deficiency is suspected. However, the disease can present at any age, and the variability of symptoms can present a diagnostic challenge to many physicians. The early recognition and treatment of APRT deficiency are of crucial importance for preventing irreversible loss of renal function, which still occurs in a nonnegligible proportion of cases. This review summarizes the genetic and metabolic mechanisms underlying stone formation and renal disease, along with the diagnosis and management of APRT deficiency.

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Section: Geneticsmentioning

confidence: 77%

Adenine Phosphoribosyltransferase Deficiency

Bollée

Harambat

Bensman

et al. 2012

Clinical Journal of the American Society of Nephrology

105

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“…The cells of DAP r variant clones and controls were washed with PBS and disrupted in 50 l buffer (50 mM Tris⅐HCl, pH 7.4͞5 mM MgCl 2 ). Measurement of APRT activity was as previously described (14).…”

Section: Methodsmentioning

confidence: 99%

Mitotic recombination produces the majority of recessive fibroblast variants in heterozygous mice

Shao

Deng

Henegariu

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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123

116

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Mice heterozygous at Aprt (adenine phosphoribosyltransferase) were used as a model to study in vivo loss of heterozygosity (LOH) in normal fibroblasts. Somatic cell variants that exhibited functional loss of the wild-type Aprt in vivo were recovered as APRT-deficient cell colonies after culturing in selection medium containing 2,6-diaminopurine (DAP), an adenine analog that is toxic only to cells with APRT enzyme activity. DAP-resistant (DAP r ) fibroblast variants were recovered at a median frequency of 12 ؋ 10 ؊5 from individual ears from progeny of crosses between mouse strains 129͞Sv and C3H͞HeJ. The frequency of DAP r variants varied greatly among individual ears, suggesting that they preexisted in vivo and arose at various times during development. Polymorphic molecular markers and a cytological marker on the centromere of chromosome 8 made it possible to discriminate between each of six possible mechanistic pathways of LOH. The majority (about 80%) of the DAP r variants were a consequence of mitotic recombination. The prevalence of mitotic recombination in regions proximal to Aprt did not correlate with meiotic map distances. In particular, there was a higher than expected frequency of crossovers within the interval 59 cM to 67 cM. The high spontaneous frequency of Aprt LOH, mediated primarily by mitotic recombination, is fully consistent with our previous results with human peripheral T cells from individuals known to be heterozygous at APRT. Thus, this Aprt heterozygote mouse is a valid model for studying somatic mutagenesis and mitotic recombination in vivo.Retinoblastoma is a prototype disease for understanding how loss of function of tumor suppressor genes (TSGs) leads to tumor formation. The so-called two-hit (two-mutational events) model explains elegantly the inheritance of genetic predisposition and development of retinal tumors (1). In familial cases, a preexisting RB1 germ-line mutation (the first hit) is inherited, predisposing the retinoblast cells to tumor development by requiring only a second mutational event (the second hit). In sporadic cases, somatic cells lack the predisposing mutation, and a retinoblast cell must acquire two separate RB1 mutations to progress to a tumor. In the two-hit model, the first hit, a rate-limiting step, renders a cell heterozygous or hemizygous at RB1. The second hit, which is frequently referred to as loss of heterozygosity (LOH), leads to the expression of the RB1 mutant phenotype (2). Because

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“…IVS4 ϩ 2insT was identified previously in several families from Europe. 2,15,18,29,30 This mutation occurred on the aprt allele carrying the polymorphic TaqI site, suggesting a founder effect 2,13 in some families but not all. 30 In the white population, two common aprt mutations show uniform associations with highly polymorphic restriction sites for TaqI and SphI, 31 namely a missense mutation in British and Icelandic patients 13,30 and IVS4 ϩ 2insT, which seems to be the most common cause of APRT deficiency among white individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Cases of APRT deficiency were only exceptionally reported in all other occidental countries, including US and European populations. 18 More than 15 years ago, we drew attention to the underdiagnosis of APRT deficiency in the white population, considering the surprisingly small number of cases reported in contrast with a homozygosity at APRT locus estimated between one in 50,000 to one in 100,000. 19 The most plausible explanation for this was that APRT deficiency may be largely unrecognized, which could be related to insufficient knowledge of the disease by clinicians involved in the treatment of patients with urolithiasis and/or renal failure.…”

Section: Discussionmentioning

confidence: 99%

Phenotype and Genotype Characterization of Adenine Phosphoribosyltransferase Deficiency

Bollée

Dollinger

Boutaud

et al. 2010

Journal of the American Society of Nephrology

111

184

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Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder causing 2,8-dihydroxyadenine stones and renal failure secondary to intratubular crystalline precipitation. Little is known regarding the clinical presentation of APRT deficiency, especially in the white population. We retrospectively reviewed all 53 cases of APRT deficiency (from 43 families) identified at a single institution between 1978 and 2009. The median age at diagnosis was 36.3 years (range 0.5 to 78.0 years). In many patients, a several-year delay separated the onset of symptoms and diagnosis. Of the 40 patients from 33 families with full clinical data available, 14 (35%) had decreased renal function at diagnosis. Diagnosis occurred in six (15%) patients after reaching ESRD, with five diagnoses made at the time of disease recurrence in a renal allograft. Eight (20%) patients reached ESRD during a median follow-up of 74 months. Thirty-one families underwent APRT sequencing, which identified 54 (87%) mutant alleles on the 62 chromosomes analyzed. We identified 18 distinct mutations. A single T insertion in a splice donor site in intron 4 (IVS4 ϩ 2insT), which produces a truncated protein, accounted for 40.3% of the mutations. We detected the IVS4 ϩ 2insT mutation in two (0.98%) of 204 chromosomes of healthy newborns. This report, which is the largest published series of APRT deficiency to date, highlights the underdiagnosis and potential severity of this disease. Early diagnosis is crucial for initiation of effective treatment with allopurinol and for prevention of renal complications.

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Mutational Basis of Adenine Phosphoribosyltransferase Deficiency

Cited by 26 publications

References 4 publications

Adenine Phosphoribosyltransferase Deficiency

Adenine Phosphoribosyltransferase Deficiency

Mitotic recombination produces the majority of recessive fibroblast variants in heterozygous mice

Phenotype and Genotype Characterization of Adenine Phosphoribosyltransferase Deficiency

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