Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2

Dinour, Dganit; Gray, Nicola K.; Ganon, Liat; Knox, Alan Β.; Shalev, Hanna; Sela, Ben‐Ami; Campbell, Susan; Sawyer, Lindsay; Shu, Xinhua; Valsamidou, Evgenia; Landau, Daniel; Wright, Alan F.; Holtzman, Eliezer J.

doi:10.1093/ndt/gfr419

Cited by 48 publications

(56 citation statements)

References 29 publications

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“…Loss of function of GLUT9 results in hypouricemia, presumably as a consequence of both a reduced release of urate from the liver and poor reabsorption from the urine in the kidney. [186][187][188][189][190][191][192] Elevated levels of plasma urate have also been associated with hypertension, gout, and metabolic disease. A number of genome-wide association studies have identif ied polymorphisms in the hSLC2A9 gene.…”

Section: Glut2: Fanconi-bickel Syndromementioning

confidence: 99%

“…However, to date, few, if any, single nucleotide polymorphisms have been demonstrated to have direct effects on the function of the protein when it is expressed in vitro. [187][188][189][190][191][192] It is more likely that such mutations have subtle effects on levels of expression or interactions with other proteins in the cell.…”

Section: Glut2: Fanconi-bickel Syndromementioning

confidence: 99%

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Structure of, and functional insight into the GLUT family of membrane transporters

Long¹,

Cheeseman²

2015

CHC

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This review examines the development of structure and function of the human GLUT proteins, gene family hSLC2A. These proteins are essential for moving the key metabolites, glucose, galactose, and fructose in and out of cells, as well as a number of other important substrates. Despite over five decades of research, it is still not fully understood how they work at the molecular level, although the recent publication of a crystal structure of GLUT1 sug-

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Section: Glut2: Fanconi-bickel Syndromementioning

confidence: 99%

Section: Glut2: Fanconi-bickel Syndromementioning

confidence: 99%

Structure of, and functional insight into the GLUT family of membrane transporters

Long¹,

Cheeseman²

2015

CHC

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“…Mutations in URAT1 and SCL2A9 result in decreased reabsorption in the proximal tubule. This results in hyperuricosuria along with low or normal serum uric acid levels (7)(8)(9). Similar mechanisms may contribute to idiopathic uric acid nephrolithiasis.…”

Section: Discussionmentioning

confidence: 98%

Results of urinary dissolution therapy for radiolucent calculi

Sinha¹,

Prabhu²,

Venkatesh³

et al. 2013

Int. braz j urol.

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Purpose: In this paper we present our experience with dissolution therapy of radiolucent calculi. Materials and Methods:This was a retrospective analysis of patients who were offered urinary dissolution therapy between January 2010 and June 2011. Patients were treated with tablets containing potassium citrate and magnesium oxide. Partial dissolution was defined as at least a 50% reduction in stone size. Patients with complete or partial dissolution were classified in the successful dissolution group. Patients with no change, inadequate reduction, increase in stone size and those unable to tolerate alkali therapy were classified as failures. Patient sex, stenting before alkalinization, stone size, urine pH at presentation and serum uric acid levels were analyzed using Fisher t-test for an association with successful dissolution. Results: Out of 67, 48 patients reported for follow up. 10 (15%) had complete dissolution and 13 (19%) had partial dissolution. Alkalinization was unsuccessful in achieving dissolution in 25 (37%). Stenting before alkalinization, patient weight (< 60 vs. > 75kg) and serum uric acid levels (≤ 6 vs. > 6) were the only factors to significantly affected dissolution rates (p = 0.039, p 0.035, p 0.01 respectively). Conclusions: A policy of offering dissolution therapy to patients with radiolucent calculi had a successful outcome in 34% of patients.

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“…2 ). Interestingly, the Arg171 residue has been previously reported by Dinour et al [9] to be substituted by a Cys residue in 3 siblings, born of consanguineous Israeli-Arab parents, with RHUC2 and without complications. In vitro functional expression studies showed that the p.Arg171Cys mutant protein had significantly reduced UA transport activity (16% of control values).…”

Section: Case Reportmentioning

confidence: 90%

“…In vitro functional expression studies showed that the p.Arg171Cys mutant protein had significantly reduced UA transport activity (16% of control values). Furthermore, homology modelling indicated that the mutation occurred in the inner channel that expels UA from the cytoplasmic to extracellular regions [9] .…”

Section: Case Reportmentioning

confidence: 99%

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

et al. 2016

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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.

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Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2

Abstract: This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.

Cited by 48 publications

References 29 publications

Structure of, and functional insight into the GLUT family of membrane transporters

Structure of, and functional insight into the GLUT family of membrane transporters

Results of urinary dissolution therapy for radiolucent calculi

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

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