Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2.
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).


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.
Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
Andrea
A
Mancikova
Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
Vladimir
V
Krylov
Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
Olha
O
Hurba
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.
Ivan
I
Sebesta
Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Makiko
M
Nakamura
Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.|Division of Kidney and Hypertension, Jikei University School of Medicine, Tokyo, Japan.
Kimiyoshi
K
Ichida
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.
Blanka
B
Stiburkova
D000293:Adolescent; D000818:Animals; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D015499:Renal Tubular Transport, Inborn Errors / Q000235:genetics*; D014545:Urinary Calculi / Q000235:genetics*; D014981:Xenopus
D051246:Glucose Transport Proteins, Facilitative; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C411811:SLC2A9 protein, human
GLUT9; Renal hypouricemia; SLC22A12; SLC2A9; URAT1; Uric acid transporters