Pediatrics & Therapeutics
Open Access

Using stem cells to understand and treat diseases due to mutations in BEST1

International Conference and Exhibition on Pediatric Cardiology

August 25-27, 2015 Valencia, Spain

Alan D Marmorstein

Mayo Clinic, USA

Posters-Accepted Abstracts: Pediat Therapeut

Abstract :

Mutations in BEST1 encoding Bestrophin 1 (Best1) causes the bestrophinopathies, a group of 5 retinal degenerative diseases including Best vitelliform macular dystrophy and autosomal recessive bestrophinopathy (ARB). Best1 is a Ca2+ activated anion channel (CAAC) that also regulates Ca2+ homeostasis. In the eye Best1 is expressed uniquely in retinal pigment epithelial (RPE) cells. Why over 200 different mutations in Best1 cause 5 distinct diseases is not clear nor is there an obvious path to treatment. To address this we are generating a bank of skin fibroblasts from patients with bestrophinopathies. The fibroblasts are reprogrammed to induced pluripotent stem cells (iPSCs) which are differentiated into retinal pigment epithelial (RPE) cells for study in the laboratory. Among our study participants are a 14 year old female with ARB and her parents. The ARB patient is compound heterozygous for Best1R141H and Best1I366fsX18. Whole cell patch clamp analysis of these Best1 mutants indicates that Best1R141H Cl-currents are impaired but that Best1R141H does not impair wild type currents. Best1I366fsX18 exhibits normal currents which are not impaired when co-expressed with Best1R141H. In iPSC derived RPE cells, neither mutant is mislocalized. These data suggest that neither loss of Best1 CAAC activity nor mislocalization of Best1 play significant roles in the pathogenesis of ARB. We are currently examining the effects of ARB mutations on Ca2+ stores and other RPE functions with the goal of using iPSC derived RPE to test the efficacy of gene augmentation, gene repair and small molecule drugs in rescuing the ARB phenotype.

Biography :

Email: amarmorstein@mayo.edu