Heterozygous Triplication of Upstream Regulatory Sequences Leads to Dysregulation of Matrix Metalloproteinase 19 (MMP19) in Patients with Cavitary Optic Disc Anomaly (CODA)

2015-01-12 00:01:29

Human Mutation; 12 JAN 2015; DOI: 10.1002/humu.22754

Ralph J. Hazlewood, Benjamin R. Roos, Frances Solivan-Timpe, Robert A. Honkanen, Lee M. Jampo, Stephen C. Gieser, Kacie J. Meyer,
Robert F. Mullins, Markus H. Kuehn, Todd E. Scheetz, Young H. Kwon, Wallace L.M. Alward, Edwin M. Stone and John H. Fingert


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 6Kbp 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 6Kbp triplication in 1 of 24 unrelated CODA patients and in none of 172 glaucoma patients. Analysis with a luciferase assay showed that the 6Kbp sequence has transcription enhancer activity. A 773bp fragment of the 6Kbp DNA segment increased downstream gene expression 8-fold, 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 which causes CODA.

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Key Words

Glaucoma | MMP19 | CODA | copy number variation | cavitary optic disc anomaly | coloboma