We report the identification of two pathogenic variants in the ABCG2 gene, encoding a urate exporter, in two probands (male and female) with severe familial gouty phenotypes and hyperuricemia. Clinico-genetic analyses identified p.I63YfsTer54 (rs565722112) and p.G74D (rs199976573) as potentially causal mutations; functional analyses demonstrated that these two variants are deficient in plasma membrane localization and functionally null. Our data show that dysfunctional variants in the ABCG2 gene are strong risk factors for hyperuricemia and gout in both males and females.

• Klíčová slova
• ABCG2, Gout, Hyperuricemia, Urate transport,
• MeSH
• ABC transportér z rodiny G, člen 2 * genetika   metabolismus   MeSH
• dna (nemoc) * genetika   metabolismus   patologie   MeSH
• hyperurikemie * genetika   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• nádorové proteiny * genetika   metabolismus   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 * MeSH
• ABCG2 protein, human MeSH Prohlížeč
• nádorové proteiny * MeSH

BACKGROUND: Heart failure (HF) is becoming an increasingly prevalent issue, particularly among the elderly population. Lipids are closely associated with cardiovascular disease (CVD) pathology. Lipidomics as a comprehensive profiling tool is showing to be promising in the prediction of events and mortality due to CVD as well as identifying novel biomarkers. MATERIALS AND METHODS: In this study, eicosanoids and lipid profiles were measured in order to predict survival in patients with de novo or acute decompensated HF. Our study included 50 patients (16 females, mean age 73 years and 34 males, mean age 71 years) with de novo or acute decompensated chronic HF with a median follow-up of 7 months. Lipids were semiquantified using targeted lipidomic liquid chromatography-mass spectrometry (LC-MS/MS) analysis. Eicosanoid concentrations were determined using a commercially available sandwich ELISA assay. RESULTS: From 736 lipids and 3 eicosanoids, 39 significant lipids were selected (by using the Mann-Whitney U test after Benjamini-Hochberg correction) with the highest number of representatives belonging to the polyunsaturated (PUFA) phosphatidylcholines (PC). PC 42:10 (p = 1.44 × 10-4) was found to be the most statistically significantly elevated in the surviving group with receiver operating characteristics of AUC = 0.84 (p = 3.24 × 10-7). A multivariate supervised discriminant analysis based on the aforementioned lipid panel enabled the classification of the groups of surviving and non-surviving patients with 90 % accuracy. CONCLUSIONS: In the present study we describe a trend in PUFA esterified in PC that were systematically increased in surviving patients with HF. This trend in low-abundant and rarely identified PUFA PC (mainly very long chain PUFA containing PC such as PC 42:10 or PC 40:9 containing FA 22:6, FA 20:5 and FA 20:4) suggests candidate biomarkers.

• Klíčová slova
• Atherosclerosis, Eicosanoids, HF survival, Heart failure, Lipidomics, PC, PUFA, Phosphatidylcholine, Survival rate,
• Publikační typ
• časopisecké články MeSH

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.

• MeSH
• dna (nemoc) * genetika   MeSH
• hyperurikemie * genetika   MeSH
• kotransportní proteiny pro sodík a fosfát - typ I * genetika   MeSH
• kyselina močová metabolismus   MeSH
• lidé MeSH
• přenašeče organických aniontů nezávislé na sodíku * genetika   MeSH
• přenašeče organických aniontů * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kotransportní proteiny pro sodík a fosfát - typ I * MeSH
• kyselina močová MeSH
• přenašeče organických aniontů nezávislé na sodíku * MeSH
• přenašeče organických aniontů * MeSH
• SLC17A1 protein, human MeSH Prohlížeč
• SLC22A11 protein, human MeSH Prohlížeč
• SLC22A13 protein, human MeSH Prohlížeč
• urate transporter MeSH Prohlížeč