Document Type

Journal Article

Date of this Version

2012

Publication Source

Retinal Degenerative Diseases: Advances in Experimental Medicine and Biology

Volume

723

Start Page

611

Last Page

618

DOI

10.1007/978-1-4614-0631-0_78

Abstract

Mutations in the bestrophin-1 gene (BEST1) are an important cause of inherited retinal disorders. Hitherto, over 100 unique allelic variants have been linked to the human BEST1 (hBEST1), and associated with disease phenotypes, broadly termed as bestrophinopathies. A spontaneous animal model recapitulating BEST1-related phenotypes, canine multifocal retinopathy (cmr), is caused by mutations in the canine gene ortholog (cBEST1). We have recently characterized molecular consequences of cmr, demonstrating defective protein trafficking as a result of G161D (cmr2) mutation. To further investigate the pathological effects of BEST1 missense mutations, canine and human peptide fragments derived from the protein sequence have been studied in silico as models for early events in the protein folding. The results showed that G161D as well as I201T substitutions cause severe conformational changes in the structure of bestrophin-1, suggesting protein misfolding as an underlying disease mechanism. The comparative modeling studies expand our insights into BEST1 pathogenesis.

Copyright/Permission Statement

The final publication is available at www.springerlink.com

Keywords

BEST1, bestrophin-1, canine multifocal retinopathy, best vitelliform macular dystrophy, comparative protein modeling, missense mutations

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Date Posted: 06 May 2015

This document has been peer reviewed.