The C421A (Q141K) polymorphism enhances the 3′-untranslated region (3′-UTR)-dependent regulation of ATP-binding cassette transporter ABCG2

Ripperger, Anne; Benndorf, Ralf A.

doi:10.1016/j.bcp.2016.02.011

Cited by 31 publications

(33 citation statements)

References 32 publications

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“…As studied in detail, the F373C variant is mostly localized in the Golgi and other intracellular compartments, while we found no apparent accumulation of any of the ABCG2 variants in the lysosomes. Previous studies have shown that the expression of the frequent ABCG2-Q141K variant is altered at several levels-reduced mRNA maturation, protein folding, membrane trafficking, and increased degradation of this protein have been suggested [24][25][26][27]. For the M71V variant our group demonstrated a reduced folding and trafficking in mammalian cells [21], while the partially defective F373C and T153M variants have not been studied as yet at the cellular level.…”

Section: Discussionmentioning

confidence: 81%

“…In 2017, several ABCG2 gene mutations were found in Europe in a cohort of gout patients [22], and while the present manuscript was under review, the same group published a further analysis of these variants in clinical samples and performed experiments to assess the expression and function of these variants [23]. In the present work we have performed a comprehensive analysis of the expression, localization, and activity of the naturally occurring M71V, R147W, T153M, K360Δ, F373C, R383C, T434M, and S476P ABCG2 variants and compared their effects to the wild-type protein, as well as to the widely present (about 20% of heterozygotes in Europe) ABCG2-Q141K polymorphism, reducing both expression and function of ABCG2 [24][25][26][27]. For large-scale rapid screening of missense ABCG2 variants we present here an efficient transient expression system, while a detailed cellular localization and processing study was performed using stable cellular ABCG2 expression.…”

Section: Introductionmentioning

confidence: 99%

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Cellular expression and function of naturally occurring variants of the human ABCG2 multidrug transporter

Zámbó

Mózner

Bartos

et al. 2019

Cell. Mol. Life Sci.

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The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno-and endobiotics; thus the relatively frequent polymorphic and mutant ABCG2 variants in the population may significantly alter disease conditions and pharmacological effects. Low-level or non-functional ABCG2 expression may increase individual drug toxicity, reduce cancer drug resistance, and result in hyperuricemia and gout. In the present work we have studied the cellular expression, trafficking, and function of nine naturally occurring polymorphic and mutant variants of ABCG2. A comprehensive analysis of the membrane localization, transport, and ATPase activity, as well as retention and degradation in intracellular compartments was performed. Among the examined variants, R147W and R383C showed expression and/or protein folding defects, indicating that they could indeed contribute to ABCG2 functional deficiency. These studies and the applied methods should significantly promote the exploration of the medical effects of these personal variants, promote potential therapies, and help to elucidate the specific role of the affected regions in the folding and function of the ABCG2 protein. Keywords ABCG2 • BCRP • MXR • Membrane transporter • Natural variants Cellular and Molecular Life Sciences Boglárka Zámbó and Orsolya Mózner contributed equally to this work.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Cellular expression and function of naturally occurring variants of the human ABCG2 multidrug transporter

Zámbó

Mózner

Bartos

et al. 2019

Cell. Mol. Life Sci.

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“…There is also strong evidence that the 141K variant protein may accumulate in aggresomes prior to its degradation 36. In addition, protein expression is also influenced by microRNAs (37 and references therein). In one example, the 3′ untranslated region truncation allows increased expression of ABCG2, removing an hsa-miR-519c binding site that blocks translation 38.…”

Section: Major Abcg2 Genetic Variantsmentioning

confidence: 99%

“…In one example, the 3′ untranslated region truncation allows increased expression of ABCG2, removing an hsa-miR-519c binding site that blocks translation 38. The 141K variant enhances the hsa-miR-519c-mediated repression of translation 37. Interestingly, the ABCG2 F142 residue is in an analogous position to the ΔF508 cystic fibrosis-causing mutation in the cystic fibrosis transmembrane receptor (encoded by ABCC7 ) 32.…”

Section: Major Abcg2 Genetic Variantsmentioning

confidence: 99%

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

Cleophas¹,

Joosten²,

Stamp³

et al. 2017

PGPM

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As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance.

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“…This extra-TA repeat decreases the rate of transcription of the UGT1A1 gene and thus decreases the enzyme activity and the glucuronidation of bilirubin [5]. Regarding the efflux transporters, we checked the presence of the functional single nucleotide polymorphisms (SNP) in the ABCC2 (-24C>T/rs717620) and ABCG2 (c.421C>A/rs2231142) genes, which have been found to influence transport activity in several studies [6,7]. Finally, as SLCO1B1 is predominantly expressed at the basolateral membrane of hepatocytes, we investigated the presence of the 521T>C variant, located in exon 5 of the gene (rs4149056), resulting in decreased uptake transport activity [8].…”

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confidence: 99%

An unexpectedly prolonged severe hyperbilirubinemia in a patient with pre-existing hepatitis A: a role of genetic predisposition?

Falvella

Angeli

Cordier

et al. 2018

Clinical Chemistry and Laboratory Medicine (CCLM)

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Acute hepatitis A virus (AHAV) infection is a self-limited condition that usually spontaneously recovers in 2-8 weeks. While in children under 6 years of age AHAV is often asymptomatic, >70% of adults manifest symptoms together with typical laboratory findings [1]. AHAV is serologically diagnosed by the detection of anti-HAV IgM, which persists 2-6 months after infection. Laboratory results during AHAV show a marked increase (usually 10 to 40 times the upper reference limit [URL]) in serum alanine aminotransferase (ALT) activity, together with high total bilirubin (TB) (average peak of 171.0 μmol/L, mainly consisting of the conjugated form) and moderately (<3 URL) increased alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) [2]. With resolution of AHAV, conjugated bilirubin (CB) is rapidly cleared and its serum concentrations return to normal quickly. However, 10%-20% of patients develop prolonged cholestasis lasting for >6 months [1].Bilirubin, which is a major end-product of heme breakdown, is physiologically glucuronidated in the liver and then excreted into the bile. The mechanisms of bilirubin excretion, and of hyperbilirubinemia causes, are

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The C421A (Q141K) polymorphism enhances the 3′-untranslated region (3′-UTR)-dependent regulation of ATP-binding cassette transporter ABCG2

Cited by 31 publications

References 32 publications

Cellular expression and function of naturally occurring variants of the human ABCG2 multidrug transporter

Cellular expression and function of naturally occurring variants of the human ABCG2 multidrug transporter

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

An unexpectedly prolonged severe hyperbilirubinemia in a patient with pre-existing hepatitis A: a role of genetic predisposition?

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