Seminar Detail

CBCB Seminar

September 16, 2024 3:30 PM

Ammon-Pinizzotto Biopharmaceutical Innovation (BPI) Building
Conference Room 140

Decoding the Mystery: The Role of ABCA4 Variants in Inherited Retinal Diseases

Esther E. Biswas-Fiss, PhD, MB(ASCP)CM

Professor and Chair, Dept. of Medical and Molecular Sciences
Director, Graduate Programs in Medical Sciences
Director, Programs in Applied Molecular Biology and Biotechnology
University of Delaware College of Health Sciences

Abstract: The ABCA4 protein, essential for vision by removing toxic retinal byproducts of phototransduction, is linked to various inherited retinal disorders (IRDs) due to its dysfunction caused by genetic variants. Functional characterization and pathogenicity assessment of the extensive number of ABCA4 variants of uncertain significance (VUS) (>900) pose a significant challenge.   This uncertainty presents three significant problems: predicting disease development in patients and their relatives, creating targeted treatments, and using genetic information for future disease prevention and participation in clinical trials. Our research aimed to identify the damaging effects of certain ABCA4 variants whose impacts were previously unknown. By combining innovative laboratory techniques with computational-based analysis, our work seeks to support ongoing efforts in genetic diagnostics and treatment strategies for improved patient outcomes. We utilized a virus-like particle (VLP)-based system for ABCA4 expression, overcoming traditional membrane protein expression limitations. We then compared the variant ABCA4-VLPs to the wild type (WT) in terms of expression level, surface localization, basal and retinal-stimulated ATPase enzymatic functions. Simultaneously, we conducted computational analyses, including protein modeling and structure analysis, to obtain multiple lines of pathogenicity evidence for ABCA4 VUS. Our analyses uncovered varying degrees of changes in localization, basal and retinal-stimulated ATPase activity associated with the variants. The computational analysis identified structural features aligning with the in vitro functional assays. This integrated approach provided substantial pathogenicity evidence and aided in reclassifying some VUS according to ACMG/AMP guidelines. This study presents the reclassification of ABCA4 VUS in IRDs through combined computational and functional analyses. The in silico approaches were instrumental in prioritizing variants and pinpointing the molecular mechanisms underlying protein dysfunction, while the VLP platform offered a streamlined method for higher-throughput in vitro variant functional characterization. Understanding the effect of variation on disease and providing accurate risk assessment will be critical to implementing precision medicine. The methodology reported here can be extended beyond ABCA4 and applied to a broader range of membrane proteins associated with other genetic disorders.

Short Bio: Esther Biswas-Fiss, PhD, MB(ASCP)^CM is a Professor and Chair of the Department of Medical and Molecular Sciences at the University of Delaware. Her scientific journey started at the University of Washington Seattle, where she studied chemistry. She earned her master’s degree in Biochemistry from the University of Maryland and then went on to earn her doctoral degree in Molecular & Cellular Pharmacology from Rutgers University. In 1999, she received her first academic appointment as a faculty member and Director of Departmental Research at Thomas Jefferson University. She was awarded a secondary faculty appointment in the Department of Ophthalmology at the Sydney Kimmel Medical College of TJU and became a member of the Wills Vision Center at Jefferson. She has served the College of Health Sciences at the University of Delaware since 2016. Esther is a member of the NIH/ClinGen ABCA4 Variant Calling Expert Panel and contributes to the review and clinical reclassification of genetic variants. Her research contributions have led to over 60 peer-reviewed publications in journals, including the European Journal of Ophthalmology, Molecular Vision, Journal of Biological Chemistry, and Biochemistry. Esther’s research focuses on understanding the consequences of genetic variation on the structure and function of proteins and their role in human health and disease, particularly the impact of genetic variants in inherited retinal degenerative diseases such as Stargardt disease.  Her research is supported by the NIH/National Eye Institute and Foundation Fighting Blindness.