title: Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Mackay
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bennett
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Shiels
mesh_terms: D001741:Black or African American / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D020090:Chromosome Segregation / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics*; D005123:Eye / Q000378:metabolism; D005190:Family; D005260:Female; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D056726:Genetic Association Studies; D008040:Genetic Linkage; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D057809:HEK293 Cells; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D034443:RNA Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger