Heterozygous triplication of upstream regulatory sequences leads to dysregulation of matrix metalloproteinase 19 in patients with cavitary optic disc anomaly

Ralph J Hazlewood; Benjamin R Roos; Frances Solivan-Timpe; Robert A Honkanen; Lee M Jampol; 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; John H Fingert

doi:10.1002/humu.22754

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Heterozygous triplication of upstream regulatory sequences leads to dysregulation of matrix metalloproteinase 19 in patients with cavitary optic disc anomaly

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Heterozygous triplication of upstream regulatory sequences leads to dysregulation of matrix metalloproteinase 19 in patients with cavitary optic disc anomaly

Ralph J Hazlewood, Benjamin R Roos, Frances Solivan-Timpe, Robert A Honkanen, Lee M Jampol, Stephen C Gieser, Kacie J Meyer, Robert F Mullins, Markus H Kuehn, Todd E Scheetz, …

Human mutation, Vol.36(3), pp.369-378

03/2015

DOI: 10.1002/humu.22754

PMCID: PMC4591753

PMID: 25581579

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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.

Matrix Metalloproteinases, Secreted - metabolism

Optic Disk - abnormalities

Pedigree

Humans

Regulatory Sequences, Nucleic Acid

Optic Disk - metabolism

Heterozygote

Chromosomes, Human, Pair 12

Glaucoma - genetics

Eye Diseases, Hereditary - metabolism

Eye Diseases, Hereditary - genetics

Details

Title: Subtitle: Heterozygous triplication of upstream regulatory sequences leads to dysregulation of matrix metalloproteinase 19 in patients with cavitary optic disc anomaly
Creators: Ralph J Hazlewood - University of Iowa
Benjamin R Roos
Frances Solivan-Timpe
Robert A Honkanen
Lee M Jampol
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
John H Fingert
Resource Type: Journal article
Publication Details: Human mutation, Vol.36(3), pp.369-378
DOI: 10.1002/humu.22754
PMID: 25581579
PMCID: PMC4591753
NLM abbreviation: Hum Mutat
ISSN: 1059-7794
eISSN: 1098-1004
Publisher: United States
Grant note: R01EY018825 / NEI NIH HHS T32 GM008629 / NIGMS NIH HHS R21 EY024621 / NEI NIH HHS R01 EY018825 / NEI NIH HHS R21 EY24621 / NEI NIH HHS R01 EY023512 / NEI NIH HHS R01EY023512 / NEI NIH HHS R01 EY022044 / NEI NIH HHS
Language: English
Date published: 03/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983979980802771

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