Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma.

Donna S Mackay,Alan Shiels,Thomas M Bennett,Anneke I Den Hollander

doi:10.1371/journal.pone.0132529

Donna S Mackay, Alan Shiels + Show 2 more

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https://doi.org/10.1371/journal.pone.0132529

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Journal: PloS one	Publication Date: Jul 10, 2015
Citations: 74	License type: CC BY 4.0

Abstract

Primary open-angle glaucoma (POAG) is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp) in exon-5 of the gene coding for epidermal growth factor (EGF) containing fibulin-like extracellular matrix protein 1 (EFEMP1) that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H) on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic.

Highlights

Glaucoma is a clinically heterogeneous group of optic neuropathies that present as progressive loss of visual field, with or without elevated intraocular pressure, characteristic excavation ('cupping') of the optic nerve head as a result of retinal ganglion cell death [1]
We investigated a three-generation African-American pedigree segregating adult-onset (35 years), primary open-angle glaucoma with manifest autosomal dominant transmission in the first two generations (Fig 1)
In this study we have identified a novel missense variant in exon-5 of EFEMP1 (c.418C>T, p.Arg140Trp) co-segregating with an autosomal dominant form of high-tension Primary open-angle glaucoma (POAG) in an African-American family

Summary

Introduction

Glaucoma is a clinically heterogeneous group of optic neuropathies that present as progressive loss of visual field, with or without elevated intraocular pressure, characteristic excavation ('cupping') of the optic nerve head as a result of retinal ganglion cell death [1]. It has been estimated that variants in at least five of the genes identified through linkage studies of Mendelian POAG (MYOC, OPTN, WDR36, CYP1B1, ASB10) may account for up to 10% of the heritability of complex POAG cases, suggesting that discovery of additional genes for monogenic forms of POAG may enhance understanding of the genetic architecture of complex POAG. It appears that genetic risk variants for the disproportionally high prevalence of POAG in anthropologically-older populations of African ancestry may differ from those in Caucasians [9,10]. We have conducted trio-based, whole-exome, massively-parallel sequencing in order to identify the genetic mutation underlying an autosomal dominant form of POAG segregating in an African-American family

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