A novel mutation in PCK2 gene causes primary angle-closure glaucoma

Abstract

Primary angle-closure glaucoma (PACG) is an ophthalmic genetic disease characterized by direct contact between the iris and trabecular meshwork, resulting in an obstructed outflow of aqueous humor from the eye. However, it is unclear as to what role genetics plays in the development of PACG. The present study investigated the disease-causing mutation in a five-generation Chinese PACG family using whole-genome sequencing. A novel heterozygous missense mutation c.977C>T in PCK2 gene was identified in five affected family members, but not in any unaffected and 86 unrelated healthy individuals. This nucleotide substitute is predicted to result in a proline to leucine substitution p.Pro326Leu. Furthermore, the function of this mutation was analyzed through various in vitro assays using the RGC-5 cell line. Our results demonstrate that the p.Pro326Leu mutation induces RGC-5 cell cycle arrest and apoptosis with a decreased BcL-XL. The increasing P53, P27, P21, AKT, and P-GSK3α were also detected in the cells transfected with c.977C>T mutation, suggesting that this mutation within PCK2 gene cause PACG through impairment of AKT/GSK3α signaling pathway.

Genetic Associations of Primary Angle-Closure Disease

“…15 Another gene, PCK2, was associated with primary angle-closure glaucoma in a Chinese pedigree. 16 In other populations, SPATA13 was associated with primary angle-closure glaucoma in a British pedigree, 18 while COL18A1 was associated with iridocorneal ZNRF3, zinc and ring finger 3. a A1 refers to effect allele, A2 refers to reference allele.…”

“…Since the first systematic review and meta-analysis on primary angle-closure disease published in 2016, a primary angle-closure glaucoma GWAS with a larger sample size and a number of new candidate gene studies have been reported. In addition, sequencing studies have identified multiple variants in coding regions associated with primary angle-closure disease or related traits . However, the association profiles for these genes or loci, including effect allele frequency, statistical significance, and effect size, varied across the study cohorts.…”

“…In addition, sequencing studies have identified multiple variants in coding regions associated with primary angleclosure disease or related traits. [9][10][11][12][13][14][15][16][17][18] However, the association profiles for these genes or loci, including effect allele frequency, statistical significance, and effect size, varied across the study cohorts. Therefore, their roles in primary angleclosure glaucoma remained inconclusive.…”

Evaluations of aqueous humor protein markers in different types of glaucoma

“…Worldwide, the number of people with glaucoma is expected to increase to 111.8 million by 2040, disproportionately affecting those residing in Asia and Africa. [1] In primary angle-closure glaucoma (PACG), the outflow pathway of the aqueous humor (AH) is obstructed anatomically by the apposition of the iris, [2] whereas in patients with primary open-angle glaucoma (POAG), ocular hypertension results from increased AH outflow resistance in the trabecular meshwork (TM), which is likely associated with increased local deposition of the extracellular matrix and stiffening of the tissue. [3][4][5] The exact mechanism underlying glaucoma pathogenesis remains unknown.…”

Mechanisms of Qing-Gan Li-Shui Formulation in Ameliorating Primary Open Angle Glaucoma: An Analysis Based on Network Pharmacology

“…RGC-5 was rst regarded as a cell line derived from rat retinal ganglion cells, but recent studies have shown that it corresponds to the mouse photoreceptor cell line 661W [9]. Despite such contamination, studies have shown that RGC-5 can still be used to test hypotheses about neural cells derived from retinal cell lines [10][11][12]. An in vitro model of chloride hexahydrate (CoCl 2 )-induced hypoxic damage in retinal ganglion cells-5 (RGC-5) reveals the pathological mechanism of glaucoma [13,14].…”