Hereditary Renal Hypouricemia Type 1 and Autosomal Dominant Polycystic Kidney Disease
Language English Country United States Media print
Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't
PubMed
26418379
DOI
10.1097/maj.0000000000000550
PII: S0002-9629(15)41297-2
Knihovny.cz E-resources
- MeSH
- Alleles MeSH
- Adult MeSH
- Genetic Linkage MeSH
- Heterozygote MeSH
- Uric Acid blood MeSH
- Humans MeSH
- Urinary Calculi complications genetics MeSH
- Mutation MeSH
- DNA Mutational Analysis MeSH
- Oocytes MeSH
- Polycystic Kidney, Autosomal Dominant complications genetics MeSH
- Organic Anion Transporters genetics MeSH
- Organic Cation Transport Proteins genetics MeSH
- Glucose Transport Proteins, Facilitative genetics MeSH
- Gene Expression Regulation MeSH
- Protein Folding MeSH
- Aged MeSH
- Gene Expression Profiling MeSH
- Renal Tubular Transport, Inborn Errors complications genetics MeSH
- Xenopus laevis MeSH
- Family Health MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
- Names of Substances
- Uric Acid MeSH
- Organic Anion Transporters MeSH
- Organic Cation Transport Proteins MeSH
- Glucose Transport Proteins, Facilitative MeSH
- SLC22A12 protein, human MeSH Browser
- SLC2A9 protein, human MeSH Browser
BACKGROUND: Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury. Type 1 is caused by a mutation in the SLC22A12 gene (URAT1) and type 2 in the SLC2A9 gene (GLUT9). In this article, the authors present a coexpression functional characterization of variants responsible for RHUC type 1 in a Czech family with polycystic kidney disease (PKD). METHODS: The serum UA concentration in the proband was 1.1 mg/dL and was expressed as an increase in the fractional excretion of UA (43%). The URAT1 allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. Linkage analysis using a panel of 4 CA-repeat flanking markers for chromosome 16 and a panel of 3 CA-repeat flanking markers for chromosome 4 was performed, which carry the PKD1 and PKD2 genes, respectively. RESULTS: Coexpression results showed that p.G366R and p.R477H suppressed urate transport by wild types. Colocalization studies showed an accumulation of URAT1 in the endoplasmic reticulum of the p.G366R variant and mainly retention of wild-type protein by variants p.G366R and p.R477H. CONCLUSIONS: The findings suggest that not only loss-of-function mutation of URAT1 but also the dominant-negative effect cause RHUC through loss of UA absorption, partly due to protein misfolding caused by accumulation of URAT1 protein in the endoplasmic reticulum.
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