Modeling the Structural Consequences of BEST1 Missense Mutations

  • Karina E. Guziewicz
  • Gustavo D. Aguirre
  • Barbara ZangerlEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


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.


BEST1 Bestrophin-1 Canine multifocal retinopathy Best vitelliform macular dystrophy Comparative protein modeling Missense mutations 



This study was supported by The Foundation Fighting Blindness, NEI/NIH grant EY06855, EY17549, The Van Sloun Fund for Canine Genetic Research, Hope for Vision, and P30EY-001583.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Karina E. Guziewicz
    • 1
  • Gustavo D. Aguirre
    • 1
  • Barbara Zangerl
    • 1
    Email author
  1. 1.Section of Ophthalmology, Department of Clinical Studies, School of Veterinary MedicineUniversity of Pennsylvania, Ryan Veterinary HospitalPhiladelphiaUSA

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