Question: 

Bestrophin-1, the gene product of BEST1, is known expressed in the retinal pigment epithelium of the eye. Mutations in BEST1 lead to Best's vitelliforme macular dystrophy, a rare autosomal inherited retinal degeneration characterized by a decreased electro-oculogram (EOG) light peak. Recent observations indicate that bestrophin-1 interacts with voltage-dependent Cav1.3 channels through their b4-subunits which possibly explains the changes in the patient's EOG. However, the influence of bestrophin-1 with disease-leading mutations on Cav1.3 ion channel is unclear.

Methods: 

Investigation of effects of the bestrophin-1 T6P mutant on Ba²⁺ currents of heterologeously expressed Cav1.3 channels. Then Cav1.3 channel currents were measured in the whole-cell configuration of the patch-clamp technique.

Results: 

In the presence of T6P mutant bestrophin-1 Cav1.3 channel currents showed smaller current density than in the presence of wild-type bestrophin-1. Furthermore, the presence of T6P mutant led to a shift in the slope of the voltage-dependent activation curve resulting in higher Cav1.3 channel activity at -40 mV. CHO cells used for patch-clamp analysis were subjected for immuno histochemistry and analyzed by confocal microscopy which revealed that the reduction in the current density probably results from an influence on the chaperone function of b4-subunits resulting in less Cav1.3 channel protein in the cell membrane.

Conclusions: 

T6P mutant bestrophin-1 changes voltage-dependence and number of Cav1.3 channels in the cell membrane. The overall reduction in Cav1.3 activity opens new routes to understand pathology of Best' disease.