title: Heterozygous triplication of upstream regulatory sequences leads to dysregulation of matrix metalloproteinase 19 in patients with cavitary optic disc anomaly.
abstract: Patients with a congenital optic nerve disease, cavitary optic disc anomaly (CODA), are born with profound excavation of the optic nerve resembling glaucoma. We previously mapped the gene that causes autosomal-dominant CODA in a large pedigree to a chromosome 12q locus. Using comparative genomic hybridization and quantitative PCR analysis of this pedigree, we report identifying a 6-Kbp heterozygous triplication upstream of the matrix metalloproteinase 19 (MMP19) gene, present in all 17 affected family members and no normal members. Moreover, the triplication was not detected in 78 control subjects or in the Database of Genomic Variants. We further detected the same 6-Kbp triplication in one of 24 unrelated CODA patients and in none of 172 glaucoma patients. Analysis with a Luciferase assay showed that the 6-Kbp sequence has transcription enhancer activity. A 773-bp fragment of the 6-Kbp DNA segment increased downstream gene expression eightfold, suggesting that triplication of this sequence may lead to dysregulation of the downstream gene, MMP19, in CODA patients. Lastly, immunohistochemical analysis of human donor eyes revealed strong expression of MMP19 in optic nerve head. These data strongly suggest that triplication of an enhancer may lead to overexpression of MMP19 in the optic nerve that causes CODA.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, Iowa.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Hazlewood
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Roos
authors.forename: Frances
authors.initials: F
authors.lastname: Solivan-Timpe
authors.forename: Robert A
authors.initials: RA
authors.lastname: Honkanen
authors.forename: Lee M
authors.initials: LM
authors.lastname: Jampol
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Gieser
authors.forename: Kacie J
authors.initials: KJ
authors.lastname: Meyer
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mullins
authors.forename: Markus H
authors.initials: MH
authors.lastname: Kuehn
authors.forename: Todd E
authors.initials: TE
authors.lastname: Scheetz
authors.forename: Young H
authors.initials: YH
authors.lastname: Kwon
authors.forename: Wallace L M
authors.initials: WL
authors.lastname: Alward
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: John H
authors.initials: JH
authors.lastname: Fingert
mesh_terms: D002881:Chromosomes, Human, Pair 12; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000378:metabolism; D005901:Glaucoma / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D009898:Optic Disk / Q000002:abnormalities* / Q000378:metabolism; D010375:Pedigree; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D053505:Matrix Metalloproteinases, Secreted; C108362:matrix metalloproteinase 19
keywords: CODA; MMP19; cavitary optic disc anomaly; coloboma; copy-number variation; glaucoma