Tags

Type your tag names separated by a space and hit enter

Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2.
Clin Exp Nephrol. 2016 Aug; 20(4):578-584.CE

Abstract

BACKGROUND

Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9).

METHODS AND RESULTS

In this article we present clinical, biochemical and molecular genetics of two Czech patients. The serum uric acid in the probands was 57 and 98 µmol/l and expressed as an increase in the fractional excretion of uric acid (40 and 18 %). The sequencing analysis of SLC22A12 and SLC2A9 revealed novel variants p.R92C and p.R203C in URAT1 and p.G72D in GLUT9. Functional studies were performed for these novel variants and for previously reported variants p.I118HfsX27, p.G216R and p.N333S in GLUT9 responsible for renal hypouricemia in three probands from Czech Republic and United Kingdom. Functional studies showed significantly decreased urate uptake for all variants. However, urate uptake of GLUT9 variants prepared for both isoforms were not significantly different.

CONCLUSIONS

This is the first complex function characterization of non-synonymous allelic variants in patients with renal hypouricemia regarding both GLUT9 isoforms. Our finding of defects in the SLC2A9 and SLC22A12 genes show the following: renal hypouricemia is not restricted to East Asia populations; urate uptake of GLUT9 variants prepared for both isoforms were not significantly different; renal hypouricemia type 2 has more wide clinical variability than type 1; the phenotypic severity of renal hypouricemia is not correlated with results of functional characterizations of URAT1 and GLUT9 variants.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Mancikova A
Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
Krylov V
Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
Hurba O
Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
Sebesta I
Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic. Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
Nakamura M
Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Ichida K
Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. Division of Kidney and Hypertension, Jikei University School of Medicine, Tokyo, Japan.
Stiburkova B
Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic. stiburkova@revma.cz. Institute of Rheumatology, Na Slupi 4, 128 50, Prague 2, Czech Republic. stiburkova@revma.cz.

MeSH

AdolescentAnimalsChildDNA Mutational AnalysisFemaleGlucose Transport Proteins, FacilitativeHumansMiddle AgedOrganic Anion TransportersOrganic Cation Transport ProteinsRenal Tubular Transport, Inborn ErrorsUrinary CalculiXenopus

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

26500098

Citation

Mancikova, Andrea, et al. "Functional Analysis of Novel Allelic Variants in URAT1 and GLUT9 Causing Renal Hypouricemia Type 1 and 2." Clinical and Experimental Nephrology, vol. 20, no. 4, 2016, pp. 578-584.
Mancikova A, Krylov V, Hurba O, et al. Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. Clin Exp Nephrol. 2016;20(4):578-584.
Mancikova, A., Krylov, V., Hurba, O., Sebesta, I., Nakamura, M., Ichida, K., & Stiburkova, B. (2016). Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. Clinical and Experimental Nephrology, 20(4), 578-584. https://doi.org/10.1007/s10157-015-1186-z
Mancikova A, et al. Functional Analysis of Novel Allelic Variants in URAT1 and GLUT9 Causing Renal Hypouricemia Type 1 and 2. Clin Exp Nephrol. 2016;20(4):578-584. PubMed PMID: 26500098.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. AU - Mancikova,Andrea, AU - Krylov,Vladimir, AU - Hurba,Olha, AU - Sebesta,Ivan, AU - Nakamura,Makiko, AU - Ichida,Kimiyoshi, AU - Stiburkova,Blanka, Y1 - 2015/10/24/ PY - 2015/06/16/received PY - 2015/10/13/accepted PY - 2015/10/27/entrez PY - 2015/10/27/pubmed PY - 2019/3/21/medline KW - GLUT9 KW - Renal hypouricemia KW - SLC22A12 KW - SLC2A9 KW - URAT1 KW - Uric acid transporters SP - 578 EP - 584 JF - Clinical and experimental nephrology JO - Clin Exp Nephrol VL - 20 IS - 4 N2 - BACKGROUND: Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). METHODS AND RESULTS: In this article we present clinical, biochemical and molecular genetics of two Czech patients. The serum uric acid in the probands was 57 and 98 µmol/l and expressed as an increase in the fractional excretion of uric acid (40 and 18 %). The sequencing analysis of SLC22A12 and SLC2A9 revealed novel variants p.R92C and p.R203C in URAT1 and p.G72D in GLUT9. Functional studies were performed for these novel variants and for previously reported variants p.I118HfsX27, p.G216R and p.N333S in GLUT9 responsible for renal hypouricemia in three probands from Czech Republic and United Kingdom. Functional studies showed significantly decreased urate uptake for all variants. However, urate uptake of GLUT9 variants prepared for both isoforms were not significantly different. CONCLUSIONS: This is the first complex function characterization of non-synonymous allelic variants in patients with renal hypouricemia regarding both GLUT9 isoforms. Our finding of defects in the SLC2A9 and SLC22A12 genes show the following: renal hypouricemia is not restricted to East Asia populations; urate uptake of GLUT9 variants prepared for both isoforms were not significantly different; renal hypouricemia type 2 has more wide clinical variability than type 1; the phenotypic severity of renal hypouricemia is not correlated with results of functional characterizations of URAT1 and GLUT9 variants. SN - 1437-7799 UR - https://www.unboundmedicine.com/medline/citation/26500098/Functional_analysis_of_novel_allelic_variants_in_URAT1_and_GLUT9_causing_renal_hypouricemia_type_1_and_2_ DB - PRIME DP - Unbound Medicine ER -