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

Yue Li,Yiqin Dai,Jing Zhang,Yidan Fan,Jianjiang Xu

doi:10.3389/fcell.2020.531986

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.

Highlights

The development of ocular anterior segment structures is a precisely coordinated process that is determined by both genetic and environmental factors
Most Peters’ anomaly (PA)-related genes are those encoding transcription factors that are expressed in the eye or other structural components, such as FOXE3, PAX6, PITX2, FOXC1, and CYP1B1 (Weisschuh et al, 2008; Arikawa et al, 2010; Mataftsi et al, 2011; Prokudin et al, 2014; Nischal, 2015), and these genes are predominantly involved in several other types of anterior segment dysgenesis (ASD) including aniridia, congenital cataract, and infantile glaucoma (Reis and Semina, 2011; Plaisancié et al, 2018; Ma et al, 2019)
The mutation detection rate was only 17.4% in isolated PA patients, which was much lower than the detection rate of other ocular diseases with strong genetic components involved (Patel et al, 2019; Zhang et al, 2019c)

Summary

Introduction

The development of ocular anterior segment structures is a precisely coordinated process that is determined by both genetic and environmental factors In humans, this process begins from week 6 of gestation, and is characterized by the formation of the lens placode from overlying surface ectoderm. With the development of next-generation sequencing (NGS), the genetic spectrum of PA has been expanded to include TFAP2A, HCCS, NDP, SLC4A11, FLNA, and COL4A1 (Deml et al, 2014; Weh et al, 2014). All these identified PA-causal genes can only explain a small proportion of the disease etiology, and most PA cases still lack a clear genetic diagnosis

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Conclusion