Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
Department of Pharmacy Practice, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-3131, Japan.
Development. 2021 Aug 15;148(16). doi: 10.1242/dev.188755. Epub 2021 Aug 26.
Mutations in ITPR1 cause ataxia and aniridia in individuals with Gillespie syndrome (GLSP). However, the pathogenic mechanisms underlying aniridia remain unclear. We identified a de novo GLSP mutation hotspot in the 3'-region of ITPR1 in five individuals with GLSP. Furthermore, RNA-sequencing and immunoblotting revealed an eye-specific transcript of Itpr1, encoding a 218amino acid isoform. This isoform is localized not only in the endoplasmic reticulum, but also in the nuclear and cytoplasmic membranes. Ocular-specific transcription was repressed by SOX9 and induced by MAF in the anterior eye segment (AES) tissues. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, in which the iris lymphatic vessels, sphincter and dilator muscles, corneal endothelium and stroma were disrupted, but the neural crest cells persisted after completion of AES formation. Our analyses revealed that the 218-amino acid isoform regulated the directionality of actin fibers and the intensity of focal adhesion. The isoform might control the nuclear entry of transcriptional regulators, such as YAP. It is also possible that ITPR1 regulates both AES differentiation and muscle contraction in the iris.
ITPR1 中的突变导致 Gillespie 综合征(GLSP)个体出现共济失调和无虹膜。然而,无虹膜的致病机制仍不清楚。我们在五个 GLSP 患者的 ITPR1 的 3'区域发现了一个新的 GLSP 突变热点。此外,RNA 测序和免疫印迹显示,Itpr1 编码一种 218 个氨基酸的异构体,具有眼部特异性转录本。这种异构体不仅定位于内质网,还定位于核和细胞质膜。SOX9 抑制眼部特异性转录,而 MAF 在眼前节(AES)组织中诱导其转录。缺失最后一个 Itpr1 外显子的 7 个碱基对的小鼠表现出共济失调和无虹膜,其中虹膜淋巴管、括约肌和扩张肌、角膜内皮和基质被破坏,但神经嵴细胞在 AES 形成完成后仍存在。我们的分析表明,218 个氨基酸的异构体调节肌动蛋白纤维的方向性和粘着斑的强度。该异构体可能控制转录调节因子(如 YAP)的核内进入。ITPR1 也可能调节 AES 分化和虹膜肌肉收缩。