Mao Mao, Kiss Márton, Ou Yvonne, Gould Douglas B
Department of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA.
Department of Genetics, University of Szeged, Középfasor 52, Szeged H-6726, Hungary.
Dis Model Mech. 2017 Apr 1;10(4):475-485. doi: 10.1242/dmm.027888. Epub 2017 Feb 24.
Ocular anterior segment dysgenesis (ASD) describes a spectrum of clinically and genetically heterogeneous congenital disorders affecting anterior structures that often lead to impaired vision. More importantly, 50-75% of patients with ASD develop early onset and aggressive glaucoma. Although several genes have been implicated in the etiology of ASD, the underlying mechanisms remain elusive. Type IV collagen alpha 1 (COL4A1) is an extracellular matrix protein and a critical component of nearly all basement membranes. mutations cause multi-system disorders in patients, including ASD (congenital cataracts, Axenfeld-Rieger's anomaly, Peter's anomaly and microphthalmia) and congenital or juvenile glaucoma. Here, we use a conditional mutation in mice to determine the location and timing of pathogenic events underlying COL4A1-related ocular dysgenesis. Our results suggest that selective expression of the mutation in neural crest cells and their derivatives is not sufficient to cause ocular dysgenesis and that selective expression of the mutation in vascular endothelial cells can lead to mild ASD and optic nerve hypoplasia but only on a sensitized background. In contrast, lens-specific expression of the conditional mutant allele led to cataracts, mild ASD and optic nerve hypoplasia, and age-related intraocular pressure dysregulation and optic nerve damage. Finally, ubiquitous expression of the conditional mutation at distinct developmental stages suggests that pathogenesis takes place before E12.5. Our results show that the lens and possibly vasculature play important roles in -related ASD and that the pathogenic events occur at mid-embryogenesis in mice, during early stages of ocular development.
眼前节发育异常（ASD）描述了一系列临床和基因异质性的先天性疾病，这些疾病会影响前部结构，常常导致视力受损。更重要的是，50%至75%的ASD患者会发生早发性和侵袭性青光眼。尽管已有多个基因与ASD的病因有关，但其潜在机制仍不清楚。IV型胶原α1（COL4A1）是一种细胞外基质蛋白，几乎是所有基底膜的关键成分。该基因突变会导致患者出现多系统疾病，包括ASD（先天性白内障、Axenfeld-Rieger异常、彼得异常和小眼症）以及先天性或青少年青光眼。在这里，我们利用小鼠的条件性突变来确定COL4A1相关眼发育异常潜在致病事件的位置和时间。我们的结果表明，在神经嵴细胞及其衍生物中选择性表达该突变不足以导致眼发育异常，而在血管内皮细胞中选择性表达该突变可导致轻度ASD和视神经发育不全，但仅在敏感背景下如此。相比之下，条件性突变等位基因在晶状体中的特异性表达导致了白内障、轻度ASD和视神经发育不全，以及与年龄相关的眼压失调和视神经损伤。最后，在不同发育阶段普遍表达条件性突变表明，致病过程发生在胚胎第12.5天之前。我们的结果表明，晶状体以及可能的脉管系统在相关ASD中起重要作用，并且致病事件发生在小鼠胚胎发育中期，即眼发育的早期阶段。
