Loss of GFAP cause retinal dysplasia and vision impairment

Abstract

ABSTRACTAlexander Disease is a rare leukodystrophy caused by gain-of-function variants in the gene encoding Glial Fibrillary Acidic Protein (GFAP), a major constituent of the intermediate filament of Astrocytes within the central nervous system. Currently, no phenotypic consequence of GFAP haploinsufficiency is known, and recent rodent experiments suggest that antisense oligonucleotide-mediated suppression of GFAP expression can reverse the disease progression in AxD.We investigated a six-generation family with ten individuals presenting with visual impairment, retinal dysplasia and pseudopapilledema. Whole genome sequencing of three affected individuals revealed a rare novel loss-of-function variant in GFAP, which segregated with disease in the family. The variant, c.928dup, results in frameshift and translation into a 422 aa protein (p.Met310Asnfs*113) wild type GFAP is 431-438 aa). Analysis of human embryonic tissues showed strong GFAP expression in retinal neural progenitors in the developing eye at 35-51 days post conception. Experiments using zebrafish models verified that the c.928dup variant does not result in extensive GFAP protein aggregation. Analysis of zebrafish loss-of-function gfap mutants, showed that depletion of GFAP causes vision impairment and retinal dysplasia, characterized by a significant loss of Müller glia cells and photoreceptor cells. Our findings provide novel insight into the function of GFAP and the consequence of GFAP deficiency.