Abstract：
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.
摘要：
ITPR1突变导致Gillespie综合征(GLSP)患者共济失调和无虹膜。然而,无虹膜的致病机制尚不清楚.我们在五个GLSP个体中的ITPR1的3'区域中确定了从头GLSP突变热点。此外，RNA测序和免疫印迹揭示了Itpr1的眼睛特异性转录物，编码218个氨基酸的同种型。这种同工型不仅位于内质网，而且在核膜和细胞质膜中。眼特异性转录被SOX9抑制，并在眼前段（AES）组织中被MAF诱导。缺乏最后一个Itpr1外显子的七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，但是AES形成完成后，神经c细胞仍然存在。我们的分析表明，218个氨基酸的同工型调节了肌动蛋白纤维的方向性和粘着斑的强度。同工型可能控制转录调节因子的核进入，比如YAP。ITPR1也可能调节虹膜中的AES分化和肌肉收缩。
