Localization and Functional Characterization of the P.Asn965Ser (N965S) ABCA4 Variant in Mice Reveal Pathogenic Mechanisms Underlying Stargardt Macular Degeneration
This week we profile a recent publication in Human Molecular Genetics from Dr. Bob Molday at the University of British Columbia.
Can you provide a brief overview of your lab’s current research focus?
Retinal degenerative diseases are a leading cause of blindness in Canada and the rest of the world population affecting 1 in 3,500 people. Current research of the Molday lab is directed toward elucidating the molecular and cellular mechanisms underlying inherited retinal degenerative diseases and using this information to design and develop novel therapeutic strategies that can prevent or slow vision loss in affected individuals. Our current focus is on Stargardt macular degeneration, an autosomal recessive disease caused by mutations in ABCA4, an ATP binding cassette (ABC) transporter that functions in the removal of toxic retinoid compounds from photoreceptor cells. Individuals with Stargardt disease typically experience a significant loss in visual acuity in their first or second decade of life and progressive loss in vision throughout life.
What is the significance of the findings in this publication?
In this paper we have generated and characterized a mouse model for Stargardt disease in which the conserved asparagine residue at position 965 in an ATP-binding binding domain of ABCA4 is replaced with serine. This disease-associated missense mutation (N965S) is commonly found in the European and Asian population and a similar mutation in a related transporter ABCA1 causes Tangiers disease, disorder associated with defective phospholipid and cholesterol efflux from cells and high density lipoprotein deficiency. Our studies show that ABCA4 harboring this mutation (N965S) is partially mislocalized in photoreceptors and devoid of functional activity. The loss in function of ABCA4 leads to the accumulation of toxic bis-retinoid compounds known to be associated with photoreceptor degeneration and vision loss in Stargardt patients.
What are the next steps for this research?
We will now use this mouse model and insights into the pathogenic mechanisms to further develop and test pharmaceutical agents (drugs) and gene replacement therapy as therapeutic treatments for Stargardt disease.
This research was funded by:
National Institutes of Health grant (EY002422) and Canadian Institutes of Health grants (PJT-148649 and PJT-378123).