Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis

Stibůrková, Blanka; Šebesta, Ivan; Ichida, Kimiyoshi; Nakamura, Makiko; Hůlková, Helena; Krylov, Vladimír; Kryspinova, Lenka; Jahnová, Helena

doi:10.1038/ejhg.2013.3

Cited by 53 publications

(67 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Differential diagnosis of HX includes all causes of hypouricemia. Similarly low levels of serum uric acid observed in our patients with HX were reported by the authors previously in patients with mutations in SLC22A12 and SLC2A9 genes causing primary renal hypouricemia [21,22]. This rare condition is a hereditary defect in uric acid transporters URAT1 (type 1) and GLUT9 (type 2) localized in proximal tubulus.…”

Section: Discussionsupporting

confidence: 79%

Modern diagnostic approach to hereditary xanthinuria

et al. 2014

Self Cite

View full text Add to dashboard Cite

Hereditary xanthinuria (HX) is a rare inherited disorder caused by a deficiency of xanthine dehydrogenase/oxidase (XDH/XO). Missing XDH/XO activity leads to undetectable levels of uric acid excessively replaced by xanthine in serum/urine. The allopurinol loading test has been traditionally used to differentiate between HX types I and II. Final confirmation of HX has been based on the biopsy finding of the absent XDH/XO activity in the small intestine or liver. We present the clinical, biochemical, ultrasound and molecular genetics findings in three new patients with HX and suggest a simple three-step approach to be used for diagnosis, typing and confirmation of HX. In the first step, the diagnosis of HX is determined by extremely low serum/urinary uric acid excessively replaced by xanthine. Second, HX is typed using urinary metabolomics. Finally, the results are confirmed by molecular genetics. We advocate for this safe and non-invasive diagnostic algorithm instead of the traditional allopurinol loading test and intestinal or liver biopsy used in the past.

show abstract

Section: Discussionsupporting

confidence: 79%

Modern diagnostic approach to hereditary xanthinuria

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…We recently identified and functionally characterized three novel variants in the SLC22A12 gene in Czech RHUC patients [4][5][6]. Our findings of two c.1245_1253del heterozygous individuals in a control cohort of 109 subjects from the Roma population suggested the existence of prevalent variant in this minority population in the Czech Republic.…”

Section: Introductionmentioning

confidence: 78%

High frequency of SLC22A12 variants causing renal hypouricemia 1 in the Czech and Slovak Roma population; simple and rapid detection method by allele-specific polymerase chain reaction

et al. 2015

Self Cite

View full text Add to dashboard Cite

Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury. Type 1 and 2 are caused by loss-of-function mutations in the SLC22A12 and SLC2A9 gene, respectively. A cohort of 881 randomly chosen ethnic Roma from two regions in Eastern Slovakia and two regions in the Czech Republic participated. Genomic DNA was isolated from buccal swabs and/or from blood samples. The c.1245_1253del and c.1400C>T genotypes were determined using polymerase chain reaction with allele-specific primers in a multiplex arrangement and/or direct sequencing of exon 7 and 9. Allele frequencies and genotypes were tested for Hardy-Weinberg equilibrium using the Chi-square test. 25 subjects were heterozygous and three were homozygous for the c.1245_1253del, while 92 subjects were heterozygous and two were homozygous for the c.1400C>T. Moreover, two participants were compound heterozygotes. Frequencies of the c.1245_1253del and c.1400C>T variants were 1.87 and 5.56 %, respectively. Our finding confirms an uneven geographical and ethnic distribution of SLC22A12 mutant variants. We found that the c.1245_1253del and c.1400C>T variants were present in the Czech and Slovak Roma population at unexpectedly high frequencies. Renal hypouricemia should be kept in mind during differential diagnostic on Roma patients with low serum uric acid concentrations.

show abstract

“…As stipulated by Stiburkova et al [13] , lack of awareness of RHUC likely allows cases to go undetected. Indeed, patients have been subjected to repeat renal biopsies when hypouricemia was not noticed at first presentation [17] .…”

Section: Discussionmentioning

confidence: 99%

“…Shortly thereafter, mutations in SLC2A9 were described in hypouricemic patients, rendering SLC2A9 another causative gene linked to RHUC [16] . When compared to patients with URAT1 mutations, individuals harbouring homozygous GLUT9 mutations exhibit more pronounced hypouricemia with FE-UA often >150%, and appear to be more vulnerable for exercise-induced AKI and nephrolithiasis [13,16] . Subjects with heterozygous GLUT9 mutations show a wider spectrum of serum UA levels, ranging from 2.0 to 4.5 mg/dl, whereas FE-UA values range from 3.2 to 21.7% in one study from Israel [16] ; these authors concluded that haploinsufficiency results in mild hypouricemia.…”

Section: Discussionmentioning

confidence: 99%

“…However, the underlying molecular defect remained obscure until Enomoto et al [12] reported the identification of the first kidney specific urate transporter URAT1 (SLC22A12) in 2002. Inactivating mutations in this gene have been subsequently found in individuals with idiopathic RHUC and >100 patients have been described, the majority being Japanese [13] . However, the existence of RHUC patients without URAT1 mutations implied the presence of additional major urate regulators [1] .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Novel Homozygous <b><i>SLC2A9</i></b> Mutation Associated with Renal-Induced Hypouricemia

et al. 2016

View full text Add to dashboard Cite

Background: Hereditary renal hypouricemia (RHUC) is a genetically heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA; acute kidney injury (AKI) and nephrolithiasis are recognized complications. Type 1 (RHUC1) is caused by mutations in the SLC22A12 gene, whereas RHUC2 is caused by mutations in the SLC2A9 gene. Patient ethnicity is diverse but only few Caucasian families with an SLC2A9 mutation have been reported. Methods: The current report describes the clinical history, biochemical and molecular genetics findings of a native Austrian family with RHUC2. The propositus presented with 2 episodes of exercise-induced AKI and exhibited profound hypouricemia. Mutational screening of the SLC22A12 and SLC2A9 genes was performed. Results: The molecular analyses revealed the homozygous c.512G>A transition that leads to the p.Arg171His missense substitution in SLC2A9, confirming the diagnosis of RHUC2. Segregation study of the causal mutation revealed that the mother and elder sister were heterozygous carriers, whereas the younger sister was found to be homozygous. Conclusion: We report the identification of a novel mutation in SLC2A9 as the cause of RHUC2 in a native Austrian family. We show that glucose transporter 9 mutations cause severe hypouricemia in homozygous individuals and confirm the high risk of AKI in male individuals harbouring these mutations. In our literature review, we provide an overview of the putative underlying pathophysiology, potential renal complications, findings on kidney biopsy as well as potential long-time renal sequelae.

show abstract

Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis

Cited by 53 publications

References 36 publications

Modern diagnostic approach to hereditary xanthinuria

Modern diagnostic approach to hereditary xanthinuria

High frequency of SLC22A12 variants causing renal hypouricemia 1 in the Czech and Slovak Roma population; simple and rapid detection method by allele-specific polymerase chain reaction

A Novel Homozygous <b><i>SLC2A9</i></b> Mutation Associated with Renal-Induced Hypouricemia

Contact Info

Product

Resources

About