Iris Malformation and Anterior Segment Dysgenesis in Mice and Humans With a Mutation in PI 3-Kinase.
Iris Malformation and Anterior Segment Dysgenesis in Mice and Humans With a Mutation in PI 3-Kinase.
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DOI：
10.1167/iovs.16-21347
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发表时间：
2017-06-01
影响因子：
4.4
通讯作者：
Kahn CR
中科院分区：
文献类型：
--
作者：
Solheim MH;Clermont AC;Winnay JN;Hallstensen E;Molven A;Njølstad PR;Rødahl E;Kahn CR
使用 SHORT 综合征（一种与人类身材矮小、脂肪营养不良、糖尿病和 Rieger 异常相关的综合征）敲入小鼠模型，确定磷脂酰肌醇 3 激酶 (PIK3R1) p85α 亚基显性失活突变对眼部的影响。我们通过体格检查、光学相干断层扫描 (OCT)、眼压测量和石蜡包埋眼睛的组织病理学切片，研究了将 p85α (PIK3R1) 中的精氨酸 649 改变为色氨酸的 SHORT 综合征杂合子突变小鼠，并将研究结果与两名患有相同突变的 SHORT 综合征杂合子人类受试者的类似研究结果进行了比较。虽然整体眼睛发育正常，角膜和晶状体透明，前房体积正常，眼压正常，视网膜结构没有变化，但敲入小鼠眼睛的 OCT 图像显示虹膜厚度和宽度显着减少，导致瞳孔面积增加和形状不规则。两名人类受试者都患有 Rieger 异常，具有相似的缺陷，包括虹膜薄和瞳孔不规则，以及突出的 Schwalbe 环、房角粘连、早期白内障形成和青光眼。尽管这两名受试者患有糖尿病超过30年，但没有出现糖尿病性视网膜病变的迹象。 PI3K p85α 调节亚基的显性失活突变会影响虹膜的发育，并导致与人类和小鼠眼前节发育不全一致的变化。
To determine the ocular consequences of a dominant-negative mutation in the p85α subunit of phosphatidylinositol 3-kinase (PIK3R1) using a knock-in mouse model of SHORT syndrome, a syndrome associated with short stature, lipodystrophy, diabetes, and Rieger anomaly in humans. We investigated knock-in mice heterozygous for the SHORT syndrome mutation changing arginine 649 to tryptophan in p85α (PIK3R1) using physical examination, optical coherence tomography (OCT), tonometry, and histopathologic sections from paraffin-embedded eyes, and compared the findings to similar investigations in two human subjects with SHORT syndrome heterozygous for the same mutation. While overall eye development was normal with clear cornea and lens, normal anterior chamber volume, normal intraocular pressure, and no changes in the retinal structure, OCT images of the knock-in mouse eyes revealed a significant decrease in thickness and width of the iris resulting in increased pupil area and irregularity of shape. Both human subjects had Rieger anomaly with similar defects including thin irides and irregular pupils, as well as a prominent ring of Schwalbe, goniosynechiae, early cataract formation, and glaucoma. Although the two subjects had had diabetes for more than 30 years, there were no signs of diabetic retinopathy. A dominant-negative mutation in the p85α regulatory subunit of PI3K affects development of the iris, and contributes to changes consistent with anterior segment dysgenesis in both humans and mice.