Novel Mutations in COL6A3 That Associated With Peters’ Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress

Abstract

Peters’ anomaly (PA) is a rare form of anterior segment dysgenesis characterized by central corneal opacity accompanied by iridocorneal or lenticulo-corneal adhesions. Although genetic mutations, particularly those affecting transcription factors that function in eye development, are known to cause PA, the etiology of this disease remains poorly understood. In this study, 23 patients with PA were recruited for panel sequencing. Four out of 23 patients were found to carry variants in known PA causal genes, PITX2 and PITX3. More importantly, two homozygous mutations (NM_057164: p.Val86Ala and p.Arg689Cys) in the COL6A3 gene (collagen type VI alpha-3 chain) that correlated with the phenotype of type I PA were identified, and then validated by following whole-exome sequencing. The expression profile of the COL6A3 gene in the cornea and the impact of the mutations on protein physiological processing and cellular function were further explored. It was shown that COL6A3 presented relatively high expression in the cornea. The mutant COL6A3 protein was relatively retained intracellularly, and its expression reduced cellular resistance to oxidative stress through an enhanced endoplasmic reticulum stress response. Taken together, our findings expanded the known genetic spectrum of PA, and provided evidence for the involvement of COL6A3 or collagen VI in ocular anterior segment development, thereby offering new insight for future investigations targeting PA.

Targeting NECTIN-1 Based on CRISPR/Cas9 System Attenuated the Herpes Simplex Virus Infection in Human Corneal Epithelial Cells In Vitro

“…Immortalized HCEC line was kindly provided by Prof. Shi Wei-yun (Shandong Eye Institute, Jinan, China) and Prof. Kaoru Araki-Sasaki (Osaka University, Osaka, Japan) and cultured as previously described. 23 Human embryonic kidney 293 T cells (HEK293T) were purchased from Cell Bank (CAS, Shanghai, China) and cultured in Dulbecco's modified Eagle medium (Gibco, Grand Island, NY, USA) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin.…”

Primary mesodermal dysgenesis of the cornea (Peter´s anomaly)

“…PA is known as Peters-plus syndrome when it presents with systemic malformations, like mental retardation, cleft lip and palate, shorter limbs, short stature, abnormal ears, and developmental delay. This syndrome is associated with homozygous mutations in the B3GLCT gene [2,4,7]. Brain imaging findings associated with PA are mainly corpus callosum abnormalities and malformations of cortical development.…”

“…In Spain, the incidence of CCO was reported as 3.11 out of 100,000 births. In the United States of America, PA represents de 65% of corneal transplants in infants and its incidence is approximately 1.5 per 100,000 live births [5,7].…”

“…Most cases are sporadic, but autosomal dominant and recessive inheritance have also been reported. Several gene mutations have been reported in PA, some of the implicated genes are FOXC1, FOXE3, PAX6, PITX2/ RIEG1, and CYP1B1 [4,7]. Faber et al recently described that a mutation in the COL4A1 gene, which encodes for collagen Ivα1, may be associated with PA [4].…”

“…Treatment of PA depends on the size, localization, laterality, and associated anomalies. Treatment options are observation, penetrating keratoplasty, controlling glaucoma and cataract surgery [1,7].…”