Mutations in the EPHA2 Gene Are a Major Contributor to Inherited Cataracts in South-Eastern Australia

Alpana Dave,Kate Laurie,Kathryn P Burdon,Sandra E Staffieri,David A Mackey,Jie Jin Wang,Deepa Taranath,Paul Mitchell,Shiwani Sharma,Jamie E Craig,Ruben Artero

doi:10.1371/journal.pone.0072518

Abstract

Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C>T in the EPHA2 gene and the previously reported splice mutation c.2826-9G>A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract.

Highlights

Cataract is an opacification of the crystalline lens
Its genetic heterogeneity is evidenced by the presence of causative mutations in at least 24 structurally and functionally important genes in the lens, with mutations in ten crystallin genes accounting for 50% of the known mutations [4]
One mutation with autosomal recessive mode of inheritance was reported in a Pakistani family [7]

Summary

Introduction

Cataract is an opacification of the crystalline lens. Congenital and juvenile cataract form a disease spectrum with presentation from birth or during early childhood and are generally referred to as congenital cataract [1]. Congenital cataract is the leading cause of childhood blindness and accounts for 1–6 and 5–15 cases per 10,000 live births respectively, in developed and poor regions of developing countries [2,3]. Inherited congenital cataract accounts for one quarter of the cases [4]. Mutations in the EPHA2 gene have been recently identified to cause congenital cataract [5,6,7,8]. Synonymous and non-synonymous variants in the EPHA2 gene have been associated with age-related cataract in multiple populations [5,10,11,12]. EPHA2 has been implicated in both congenital and age-related cataract suggesting a vital role of this gene in lens development and in maintaining lens cell homeostasis and transparency

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Results