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Heterozygous Triplication of Upstream Regulatory Sequences Leads to Dysregulation of Matrix Metalloproteinase 19 in Patients with Cavitary Optic Disc Anomaly
Author(s) -
Hazlewood Ralph J.,
Roos Benjamin R.,
SolivanTimpe Frances,
Honkanen Robert A.,
Jampol Lee M.,
Gieser Stephen C.,
Meyer Kacie J.,
Mullins Robert F.,
Kuehn Markus H.,
Scheetz Todd E.,
Kwon Young H.,
Alward Wallace L.M.,
Stone Edwin M.,
Fingert John H.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22754
Subject(s) - biology , locus (genetics) , optic nerve , glaucoma , gene , coda , gene duplication , enhancer , genetics , microbiology and biotechnology , gene expression , anatomy , neuroscience , seismology , geology
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 D atabase of G enomic V ariants. 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 MMP 19 in optic nerve head. These data strongly suggest that triplication of an enhancer may lead to overexpression of MMP 19 in the optic nerve that causes CODA .