A novel GFAP frameshift variant identified in a family with optico-retinal dysplasia and vision impairment

• Published in: Human molecular genetics
• Main Authors: Sarusie, Menachem V K, Rönnbäck, Cecilia, Jespersgaard, Cathrine, Baungaard, Sif, Ali, Yeasmeen, Kessel, Line, Christensen, Søren T, Brøndum-Nielsen, Karen, Møllgård, Kjeld, Rosenberg, Thomas, Larsen, Lars A, Grønskov, Karen
• Format: Journal Article
• Language: English
• Published: England 29.10.2024
• Subjects: optico-retinal dysplasia; Hereditary; Alexander’s disease; GFAP
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddae134

Gain-of-function variants in GFAP leads to protein aggregation and is the cause of the severe neurodegenerative disorder Alexander Disease (AxD), while loss of GFAP function has been considered benign. Here, we investigated a six-generation family, where multiple individuals presented with gliosis of the optic nerve head and visual impairment. Whole genome sequencing (WGS) revealed a frameshift variant in GFAP (c.928dup, p.(Met310Asnfs*113)) segregating with disease. Analysis of human embryonic tissues revealed strong expression of GFAP in retinal neural progenitors. A zebrafish model verified that c.928dup does not result in extensive GFAP protein aggregation and zebrafish gfap loss-of-function mutants showed vision impairment and retinal dysplasia, characterized by a significant loss of Müller glia cells and photoreceptor cells. Our findings show how different mutational mechanisms can cause diverging phenotypes and reveal a novel function of GFAP in vertebrate eye development.