Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration

Authors:
Publisher website
Google Scholar
Abstract
Stargardt macular degeneration (STGD1) is caused by mutations in the gene encoding ABCA4, an ATP‐binding cassette protein that transports N‐retinylidene‐phosphatidylethanolamine (N‐Ret‐PE) across photoreceptor membranes. Reduced ABCA4 activity results in retinoid accumulation leading to photoreceptor degeneration. The disease onset and severity vary from severe loss in visual acuity in the first decade to mild visual impairment late in life. We determined the effect of 22 disease‐causing missense mutations on the expression and ATPase activity of ABCA4 in the absence and presence of N‐Ret‐PE. Three classes were identified that correlated with the disease onset in homozygous STGD1 individuals: Class 1 exhibited reduced ABCA4 expression and ATPase activity that was not stimulated by N‐Ret‐PE; individuals homozygous for these variants had an early disease onset (≤ 13 yr); Class 2 showed reduced ATPase activity with limited stimulation by N‐Ret‐PE; these correlated with a moderate disease onset (14 – 40 yr); Class 3 displayed high expression and ATPase activity that was strongly activated by N‐Ret‐PE; these were associated with a late disease onset (> 40 yr). Based on our results, we introduce a functionality index for gauging the effect of missense mutations on STGD1 severity. Our studies support the mild phenotype exhibited by the p.Gly863Ala, p.Asn1868Ile, and p.Gly863Ala/p.Asn1868Ile variants.
Funding Information
  • National Eye Institute (EY002422)

This publication has 58 references indexed in Scilit: