Abstract The ABCG2 membrane protein is a key xeno- and endobiotic transporter, modulating the absorption and metabolism of pharmacological agents and causing multidrug resistance in cancer. ABCG2 is also involved in uric acid elimination and its impaired function is causative in gout.
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Analysis of ABCG2 expression in the erythrocyte membranes of care pathway for newly diagnosed type 2 diabetes volunteers and gout patients showed an enrichment of lower expression levels in the patients. By genetic screening based on protein expression, we found a relatively frequent, novel ABCG2 mutation ABCG2-M71Vwhich, according to cellular expression studies, causes reduced protein expression, although with preserved transporter capability.
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Molecular dynamics simulations indicated a stumbled dynamics of the mutant protein, while ABCG2-M71V expression in vitro could be corrected by therapeutically relevant small molecules. These results suggest that personalized medicine should consider this newly discovered ABCG2 mutation, and genetic analysis linked to protein expression provides a new tool to uncover clinically important mutations in membrane proteins.
Introduction ABCG2 belongs to the ATP-binding cassette ABC transporter family and plays an important role in the extrusion of care pathway for newly diagnosed type 2 diabetes variety of harmful compounds from our cells, protecting our body against xeno- and endobiotics, as a key participant in the so-called chemoimmunity system 1. This protein is physiologically highly expressed in the liver 2the intestine 3the blood-brain-barrier 4and the placenta 5with the role of eliminating various drugs and toxic materials, including the products of porphyrin and steroid metabolism, as well as uric acid 67.
Moreover, in pharmacological treatments of various diseases, the ABCG2 protein plays an important role in modulating drug absorption, distribution, metabolism, excretion and toxicity ADME-Tox properties 8.
In addition, ABCG2 may also be responsible for cancer multidrug resistance, as its overexpression allows tumor cells to remove chemotherapeutic agents 9 — ABCG2 expression in the kidney proximal tubules and in the enterocytes has a key role in the systemic excretion of uric acid, and genome-wide association studies GWAS showed a significant link between gout and genetic variations in ABCG2 12 — This ABCG2 variant has an impaired folding and cellular processing; thus, its plasma membrane expression is reduced In addition to the ABCG2-QK variant, other, less frequent SNPs or mutations may significantly affect the expression, function, or cellular trafficking of the transporter.
Some of these variants have already been characterized see Suppl.
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Thus, it is an insurmountable task to identify variants with an effect on protein function, expression, and trafficking. The recognition of specific genetic variants causing altered membrane protein expression could be significantly promoted by direct protein measurements in easily accessible human tissues.
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It has been shown recently that the erythrocyte membrane protein expression profile may serve as an information platform in this regard. The membrane protein expression levels depend on both genetic factors 19 — 21and regulatory alterations 22 ; thus, the erythrocyte membrane protein levels can be regarded as medically useful biomarkers.
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Recently, we have developed a simple, fast, and reliable flow cytometry method, which allows to quantitate numerous erythrocyte membrane proteins from only a drop of blood We have also shown that reduced levels of the erythrocyte membrane ABCG2 19 or ABCB6 20caused by genetic alterations, can be properly determined by using this technology.
In the present study, we have examined the expression levels of the ABCG2 protein in healthy volunteers, gout patients, as well as kezelés.
diabetes babér lap clinical control subjects, and mapped the genetic background of the altered ABCG2 expression levels in DNA samples. We specifically examined gout patients in this regard because of a higher ABCG2 mutation rate expected in this disease Additionally, we also screened about healthy blood donors for establishing the population-level frequency of the genetic variations found.
In addition to already described ABCG2 polymorphisms and mutations, we found a novel and relatively frequent missense mutation, ABCG2-M71V, with a low erythrocyte membrane sugar cukorbetegség kezelésében expression level. We have performed detailed in vitro cellular expression studies for this variant, and found a strongly reduced overall and membrane ABCG2 expression.
Molecular dynamics analysis of the ABCG2-M71V protein, based on the recently described atomic level structure of the ABCG2 transporter see refs 25 — 28revealed an altered residue interaction pattern and a stumbled correlation of motions in the mutant form of the transporter.
Results Quantitative ABCG2 protein expression measurements in erythrocytes, mutation studies In these experiments we have studied blood samples of a large group of normal, healthy volunteers under the age of 60 years, a group of patients 64 with clinically established hyperuricemia or gout, as well as of an age-matched control group 37 with unrelated orthopedic problems, treated at the same clinic see Methods.
In DNA samples of these groups, we performed molecular genetic analysis of the ABCG2 gene, screening for the known, major polymorphism QK, and for the mutations observed by sequencing the DNA samples of donors showing lower than average ABCG2 protein expression in the erythrocyte membrane. For the location of the most important mutations and polymorphism in the protein, see the scheme in Suppl.
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Figure 1. As shown, this polymorphism, either in a heterozygous or in a homozygous form, was more frequent in individuals with low ABCG2 expression.
As documented in Fig.