INTRODUCTION: Microphthalmia syndromic 12 (MCOPS12) is a rare neurologic disease caused by the point mutations of Retinoic Acid Receptor β (RARβ). It affects striatum, eyes and selected internal organs. Regulation of the retinoic acid (RA) pathway is crucial for their development. The disease is linked to mutations in RARβ and is caused by its de novo mutation. In collaboration with clinicians, team has generated and validated mouse models for MCOPS12. Mice like patients display motor and cognitive deficits . We found that MCOPS12 mouse model displays defect in cholesterol brain metabolism. The clearance of excess cholesterol from the brain involves enzyme cyp46A1. It is responsible for catalyzing reaction of cholesterol is conversion into 24-hydroxycholesterol.

AIM(S): Identification of the mechanisms and diagnostic markers in MCOPS12 to orient potential treatment strategies to deliver and help scientific community as well as affected patients to broaden the understanding of the matter.

METHOD(S): Primary neuronal cultures were established from Wt and RARb mice carrying null mutation (KO) or disease causing R387C point mutation, cultured for 7 days and used for immunofluorescenct analyses of protein expression (IF) combined with determination of cholesterol localization.

RESULTS: IF analyses showed difference in cyp46A1 expression between mutants and WT as well as cholesterol intracellular distribution. Lysosomal changes were also observed and potentially associated with abnormal cholesterol distribution in mutant mice. This was associated with altered acid alpha-glucosidase (GAA) amount that were also observed to be affected in mutant mice

CONCLUSIONS: Investigations in this area can put more light into topic of rare diseases expanding understanding of the processes behind them and help finding treatment strategies.

FINANCIAL SUPPORT: Wrocław University of Science and Technology PhD scholarship BGF - French government scholarship Cure MCOPS12 foundation