Author(s): Viktoria Prantner, Yuval Cinnamon, Jenni KÃ¼blbeck, Ferdinand MolnÃ¡r,and Paavo Honkakoski
The nuclear receptor constitutive androstane receptor (CAR; NR1I3) controls the inducible expression of many enzymes and transporters involved in drug metabolism and transport, energy metabolism and toxicity. Single nucleotide variants of CAR are quite rare and usually associated with changes in pharmacokinetics of therapeutic drugs. Recently, a nonsynonymous variant (F243S in the wild-type CAR) has been linked to the Kleefstra syndrome (MIM 610253) affecting neurological development. We identified another, previously unknown CAR variant (I281T) in a patient suffering from Kleefstra-like symptoms. Detailed reporter gene assays and molecular modelling indicated that the I281T mutation decreases the ability of CAR to recruit co-activators, likely by interfering with the assembly of functional CAR/retinoid X receptor (RXR) heterodimers. Although the I281T variant does not seem to cause the features of the patient, the present study adds to our knowledge about CAR function.