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Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane

Boglárka Zámbó1, Zsuzsa Bartos1, Orsolya Mózner1

  • 1Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary.

Scientific Reports
|May 12, 2018
PubMed

Insights

A novel ABCG2 mutation (ABCG2-M71V) reduces transporter protein expression, impacting gout and drug resistance. This discovery highlights the need for personalized medicine considering genetic variations in membrane proteins.

Area of Science:

  • Biochemistry and Molecular Biology
  • Pharmacogenomics
  • Membrane Transport Proteins

Background:

  • The ATP-binding cassette subfamily G member 2 (ABCG2) is a crucial transporter protein involved in xenobiotic and endobiotic transport.
  • ABCG2 dysfunction is implicated in conditions such as gout and multidrug resistance in cancer.
  • Reduced ABCG2 expression has been observed in erythrocyte membranes of gout patients.

Purpose of the Study:

  • To identify novel mutations in ABCG2 associated with altered protein expression.
  • To investigate the functional consequences of identified mutations on ABCG2 transport activity.
  • To explore potential therapeutic strategies for ABCG2-related disorders.

Main Methods:

  • Analysis of ABCG2 expression in erythrocyte membranes from healthy volunteers and gout patients.
  • Genetic screening to identify ABCG2 mutations based on protein expression levels.
  • In vitro cellular expression studies to assess the impact of mutations on protein expression and function.
  • Molecular dynamics simulations to elucidate the structural and dynamic effects of mutations.
  • Testing of small molecules for their ability to correct mutant ABCG2 expression.

Main Results:

  • A novel, relatively frequent ABCG2 mutation, ABCG2-M71V, was identified.
  • Cellular expression studies revealed that ABCG2-M71V leads to reduced protein expression but retains transporter capability.
  • Molecular dynamics simulations suggested altered protein dynamics for the ABCG2-M71V mutant.
  • Therapeutically relevant small molecules demonstrated the ability to correct ABCG2-M71V expression in vitro.

Conclusions:

  • The ABCG2-M71V mutation is a significant finding with implications for gout and cancer treatment.
  • Genetic analysis combined with protein expression profiling is a valuable approach for discovering clinically relevant membrane protein mutations.
  • Personalized medicine strategies should incorporate the identification of specific ABCG2 mutations for tailored therapeutic interventions.

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