Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1C variant (c.52G > T/p.Glu18Ter/rs143174402). This gene encodes GCAP3, a member of the guanylate cyclase activating protein family, involved in phototransduction and with a potential role in intraocular pressure regulation. Segregation analysis supported the notion that the variant was coinherited with the disease in an autosomal recessive fashion. GCAP3 was detected immunohistochemically in the adult human ocular ciliary epithelium and retina. To evaluate the ocular effect of GUCA1C loss-of-function, a guca1c knockout zebrafish line was generated by CRISPR/Cas9 genome editing. Immunohistochemistry demonstrated the presence of GCAP3 in the non-pigmented ciliary epithelium and retina of adult wild-type fishes. Knockout animals presented up-regulation of the glial fibrillary acidic protein in Müller cells and evidence of retinal ganglion cell apoptosis, indicating the existence of gliosis and glaucoma-like retinal damage. In summary, our data provide evidence for the role of GUCA1C as a candidate gene in PCG and offer new insights into the function of this gene in the ocular anterior segment and the retina.

中文翻译：

---

GUCA1C 在原发性先天性青光眼和视网膜中的作用：斑马鱼的功能评估

原发性先天性青光眼 (PCG) 是一种异质性、遗传性和严重的视神经病变，由视网膜神经节细胞层的凋亡变性引起。对一个 PCG 家族的全外显子组测序分析确定了两个携带低频纯合无义 GUCA1C 变异（c.52G > T/p.Glu18Ter/rs143174402）的受影响兄弟姐妹。该基因编码 GCAP3，鸟苷酸环化酶激活蛋白家族的成员，参与光转导并在眼内压调节中具有潜在作用。分离分析支持该变异以常染色体隐性方式与疾病共同遗传的观点。在成人眼睫状上皮和视网膜中通过免疫组织化学检测到 GCAP3。为了评估 GUCA1C 功能丧失的眼部影响，guca1c 敲除斑马鱼系是通过 CRISPR/Cas9 基因组编辑生成的。免疫组织化学证明 GCAP3 在成年野生型鱼类的无色素睫状上皮和视网膜中存在。敲除动物表现出 Müller 细胞中胶质纤维酸性蛋白的上调和视网膜神经节细胞凋亡的证据，表明存在胶质增生和青光眼样视网膜损伤。总之，我们的数据为 GUCA1C 作为 PCG 中候选基因的作用提供了证据，并为该基因在眼前节和视网膜中的功能提供了新的见解。敲除动物表现出 Müller 细胞中胶质纤维酸性蛋白的上调和视网膜神经节细胞凋亡的证据，表明存在胶质增生和青光眼样视网膜损伤。总之，我们的数据为 GUCA1C 作为 PCG 中候选基因的作用提供了证据，并为该基因在眼前节和视网膜中的功能提供了新的见解。敲除动物表现出 Müller 细胞中胶质纤维酸性蛋白的上调和视网膜神经节细胞凋亡的证据，表明存在胶质增生和青光眼样视网膜损伤。总之，我们的数据为 GUCA1C 作为 PCG 中候选基因的作用提供了证据，并为该基因在眼前节和视网膜中的功能提供了新的见解。