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
Department of Clinical Genetics, Kennedy Center, Rigshospitalet, University of Copenhagen, Gamle Landevej 7, 2600 Glostrup, Denmark.
Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
Hum Mol Genet. 2024 Dec 6;33(24):2145-2158. 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.
胶质纤维酸性蛋白（GFAP）的功能获得性变异会导致蛋白质聚集，是严重神经退行性疾病亚历山大病（AxD）的病因，而GFAP功能丧失一直被认为是良性的。在此，我们研究了一个六代家族，其中多名个体出现视神经乳头胶质增生和视力损害。全基因组测序（WGS）揭示了GFAP中的一个移码变异（c.928dup，p.(Met310Asnfs*113)）与疾病共分离。对人类胚胎组织的分析显示GFAP在视网膜神经祖细胞中强烈表达。斑马鱼模型证实c.928dup不会导致广泛的GFAP蛋白聚集，而斑马鱼gfap功能丧失突变体表现出视力损害和视网膜发育异常，其特征是米勒胶质细胞和光感受器细胞显著减少。我们的研究结果展示了不同的突变机制如何导致不同的表型，并揭示了GFAP在脊椎动物眼睛发育中的新功能。
