ArticleHuman mutation2015
Heterozygous triplication of upstream regulatory sequences leads to dysregulation of matrix metalloproteinase 19 in patients with cavitary optic disc anomaly.
Article in Human mutation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 13 citations in OpenAlex.
- Serous maculopathy in congenital cavitary optic disc anomaly: A case series.American journal of ophthalmology case reports · 2025Article
- Functional categorization of gene regulatory variants that cause Mendelian conditions.Human genetics · 2024Review
- Progressive optic nerve changes in cavitary optic disc anomaly: integration of copy number alteration and cis-expression quantitative trait loci to assess disease etiology.BMC medical genetics · 2019Article
- A large family with inherited optic disc anomalies: a correlation between a new genetic locus and complex ocular phenotypes.Scientific reports · 2017Article
- Assessment of a three-generation pedigree with Fuchs endothelial corneal dystrophy with anticipation for expansion of the triplet repeat in the TCF4 gene.Eye (London, England) · 2017Article
- Metalloproteinases as mediators of inflammation and the eyes: molecular genetic underpinnings governing ocular pathophysiology.International journal of ophthalmology · 2017Review
- Biochemical and Biological Attributes of Matrix Metalloproteinases.Progress in molecular biology and translational science · 2017Review
- MMP19 expression in the human optic nerve.Molecular vision · 2016Article
- Familial Optic Disc Pits in 2 Father-Son Pairs: Clinical Features and Genetic Analysis.Case reports in ophthalmologyArticle
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.