• Something wrong with this record ?

Examining the Association of Rare Allelic Variants in Urate Transporters SLC22A11, SLC22A13, and SLC17A1 with Hyperuricemia and Gout

J. Vávra, K. Pavelcová, J. Mašínová, L. Hasíková, E. Bubeníková, A. Urbanová, A. Mančíková, B. Stibůrková

. 2024 ; 2024 (-) : 5930566. [pub] 20240106

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24007637

Genetic variations in urate transporters play a significant role in determining human urate levels and have been implicated in developing hyperuricemia or gout. Polymorphism in the key urate transporters, such as ABCG2, URAT1, or GLUT9 was well-documented in the literature. Therefore in this study, our objective was to determine the frequency and effect of rare nonsynonymous allelic variants of SLC22A11, SLC22A13, and SLC17A1 on urate transport. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined all coding regions and exon-intron boundaries of SLC22A11, SLC22A13, and SLC17A1 using PCR amplification and Sanger sequencing. For comparison, we used a control group consisting of 115 normouricemic subjects. To examine the effects of the rare allelic nonsynonymous variants on the expression, intracellular processing, and urate transporter protein function, we performed a functional characterization using the HEK293A cell line, immunoblotting, fluorescent microscopy, and site directed mutagenesis for preparing variants in vitro. Variants p.V202M (rs201209258), p.R343L (rs75933978), and p.P519L (rs144573306) were identified in the SLC22A11 gene (OAT4 transporter); variants p.R16H (rs72542450), and p.R102H (rs113229654) in the SLC22A13 gene (OAT10 transporter); and the p.W75C variant in the SLC17A1 gene (NPT1 transporter). All variants minimally affected protein levels and cytoplasmic/plasma membrane localization. The functional in vitro assay revealed that contrary to the native proteins, variants p.P519L in OAT4 (p ≤ 0.05), p.R16H in OAT10 (p ≤ 0.05), and p.W75C in the NPT1 transporter (p ≤ 0.01) significantly limited urate transport activity. Our findings contribute to a better understanding of (1) the risk of urate transporter-related hyperuricemia/gout and (2) uric acid handling in the kidneys.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc24007637
003      
CZ-PrNML
005      
20240423160141.0
007      
ta
008      
240412e20240106xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1155/2024/5930566 $2 doi
035    __
$a (PubMed)38222853
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Vávra, Jiří $u Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000165477625
245    10
$a Examining the Association of Rare Allelic Variants in Urate Transporters SLC22A11, SLC22A13, and SLC17A1 with Hyperuricemia and Gout / $c J. Vávra, K. Pavelcová, J. Mašínová, L. Hasíková, E. Bubeníková, A. Urbanová, A. Mančíková, B. Stibůrková
520    9_
$a Genetic variations in urate transporters play a significant role in determining human urate levels and have been implicated in developing hyperuricemia or gout. Polymorphism in the key urate transporters, such as ABCG2, URAT1, or GLUT9 was well-documented in the literature. Therefore in this study, our objective was to determine the frequency and effect of rare nonsynonymous allelic variants of SLC22A11, SLC22A13, and SLC17A1 on urate transport. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined all coding regions and exon-intron boundaries of SLC22A11, SLC22A13, and SLC17A1 using PCR amplification and Sanger sequencing. For comparison, we used a control group consisting of 115 normouricemic subjects. To examine the effects of the rare allelic nonsynonymous variants on the expression, intracellular processing, and urate transporter protein function, we performed a functional characterization using the HEK293A cell line, immunoblotting, fluorescent microscopy, and site directed mutagenesis for preparing variants in vitro. Variants p.V202M (rs201209258), p.R343L (rs75933978), and p.P519L (rs144573306) were identified in the SLC22A11 gene (OAT4 transporter); variants p.R16H (rs72542450), and p.R102H (rs113229654) in the SLC22A13 gene (OAT10 transporter); and the p.W75C variant in the SLC17A1 gene (NPT1 transporter). All variants minimally affected protein levels and cytoplasmic/plasma membrane localization. The functional in vitro assay revealed that contrary to the native proteins, variants p.P519L in OAT4 (p ≤ 0.05), p.R16H in OAT10 (p ≤ 0.05), and p.W75C in the NPT1 transporter (p ≤ 0.01) significantly limited urate transport activity. Our findings contribute to a better understanding of (1) the risk of urate transporter-related hyperuricemia/gout and (2) uric acid handling in the kidneys.
650    _2
$a lidé $7 D006801
650    12
$a dna (nemoc) $x genetika $7 D006073
650    12
$a hyperurikemie $x genetika $7 D033461
650    12
$a přenašeče organických aniontů $x genetika $7 D027361
650    12
$a přenašeče organických aniontů nezávislé na sodíku $x genetika $7 D029362
650    _2
$a kyselina močová $x metabolismus $7 D014527
650    12
$a kotransportní proteiny pro sodík a fosfát - typ I $x genetika $7 D050609
655    _2
$a časopisecké články $7 D016428
700    1_
$a Pavelcová, Kateřina $u Institute of Rheumatology, Prague, Czech Republic $1 https://orcid.org/0000000253797282 $7 xx0228018
700    1_
$a Mašínová, Jana $u Institute of Rheumatology, Prague, Czech Republic $1 https://orcid.org/0000000274461542
700    1_
$a Hasíková, Lenka $u Institute of Rheumatology, Prague, Czech Republic $1 https://orcid.org/0000000247942252
700    1_
$a Bubeníková, Eliška $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic
700    1_
$a Urbanová, Aneta $u 1st Department of Medicine, Department of Hematology; First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
700    1_
$a Mančíková, Andrea $u Department of Staphylococcal and Food-Borne Bacterial Infections, The National Institute of Public Health, Prague, Czech Republic $1 https://orcid.org/0000000344871943
700    1_
$a Stibůrková, Blanka $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic $u Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic $1 https://orcid.org/0000000324651476 $7 xx0056517
773    0_
$w MED00001413 $t Disease markers $x 1875-8630 $g Roč. 2024 (20240106), s. 5930566
856    41
$u https://pubmed.ncbi.nlm.nih.gov/38222853 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20240412 $b ABA008
991    __
$a 20240423160137 $b ABA008
999    __
$a ok $b bmc $g 2081557 $s 1217404
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2024 $b 2024 $c - $d 5930566 $e 20240106 $i 1875-8630 $m Disease markers $n Dis Markers $x MED00001413
LZP    __
$a Pubmed-20240412

Find record

Citation metrics

Archiving options