Functional characterization of six SLCO1B1 (OATP1B1) variants observed in Finnish individuals with a psychotic disorder

Abstract

AimVariants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. MethodsThe SUPER-Finland study has performed exome sequencing on 9,381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled Combined Annotation-Dependent (CADD) scores and the Ensembl variant effect predictor (VEP). In vitro functionality studies were conducted for the SNVs with PHRED-scaled CADD score >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2,7-dichlorofluorescein (DCF) in OATP1B1 expressing HEK293 cells was measured. The amount of OATP1B1 in crude membrane fractions was quantified with a LC-MS/MS-based quantitative targeted absolute proteomics analysis. ResultsSix rare missense variants of SLCO1B1 were identified in the study population located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in protein loss of function, abolishing the uptake of DCF and reducing membrane protein expression to 31% of reference OATP1B1. ConclusionsOf the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes loss-of-function of OATP1B1 transport and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T may be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and may have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/22278615v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@15cb149org.highwire.dtl.DTLVardef@7b5125org.highwire.dtl.DTLVardef@c6af3org.highwire.dtl.DTLVardef@141a2a0_HPS_FORMAT_FIGEXP M_FIG C_FIG