Alexander disease results from gain-of-function mutations in the gene encoding glial fibrillary acidic protein (GFAP). At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ∼90% of GFAP protein. We describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre-messenger RNA (mRNA) and result in the upregulation of a previously uncharacterized GFAP lambda isoform (NM_001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM_001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM_001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini-gene splicing reporter assay, we demonstrate both variants result in the upregulation of the lambda isoform. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing to inform future pathophysiologic and therapeutic study for Alexander disease.

中文翻译：

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II 型亚历山大病是由剪接错误和未表征的 GFAP 亚型异常过度表达引起的。


亚历山大病是由编码胶质纤维酸性蛋白 (GFAP) 的基因的功能获得性突变引起的。至少有八种 GFAP 亚型已被描述，然而，主要的 α 亚型占 GFAP 蛋白的~90%。我们描述了在 II 型亚历山大病的三个不相关家族中发现的外显子变异，这些变异改变了 GFAP 前信使 RNA (mRNA) 的剪接，并导致先前未表征的 GFAP lambda 同工型 (NM_001363846.1) 上调。家族 1 和家族 2 的受影响成员具有相同的错义变体 NM_001363846.1:c.1289G>A;p.(Arg430His)，而在家族 3 中，我们在相邻核苷酸中鉴定出同义变体 NM_001363846.1:c.1290C >A;p.(Arg430Arg)。通过对脑尸检样本进行 RNA 和蛋白质分析，以及微型基因剪接报告基因检测，我们证明这两种变异都会导致 lambda 同工型的上调。我们的方法证明了表征 GFAP 变异对 mRNA 剪接的影响的重要性，为未来亚历山大病的病理生理学和治疗研究提供信息。