PUBLICATION
Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease
- Authors
- Ghiasvand, N.M., Rudolph, D.D., Mashayekhi, M., Brzezinski, J.A., Goldman, D., and Glaser, T.
- ID
- ZDB-PUB-110429-10
- Date
- 2011
- Source
- Nature Neuroscience 14(5): 578-586 (Journal)
- Registered Authors
- Goldman, Dan
- Keywords
- none
- MeSH Terms
-
- Male
- Magnetic Resonance Imaging
- Retina/cytology*
- Retina/embryology
- DNA Mutational Analysis
- PubMed
- 21441919 Full text @ Nat. Neurosci.
Abstract
Individuals with nonsyndromic congenital retinal nonattachment (NCRNA) are totally blind from birth. The disease afflicts <1% of Kurdish people living in a group of neighboring villages in North Khorasan, Iran. We found that NCRNA is caused by a 6,523-bp deletion that spans a remote cis regulatory element 20 kb upstream from ATOH7 (Math5), a bHLH transcription factor gene that is required for retinal ganglion cell (RGC) and optic nerve development. In humans, the absence of RGCs stimulates massive neovascular growth of fetal blood vessels in the vitreous and early retinal detachment. The remote ATOH7 element appears to act as a secondary or 'shadow' transcriptional enhancer. It has minimal sequence similarity to the primary enhancer, which is close to the ATOH7 promoter, but drives transgene expression with an identical spatiotemporal pattern in the mouse retina. The human transgene also functions appropriately in zebrafish, reflecting deep evolutionary conservation. These dual enhancers may reinforce ATOH7 expression during early critical stages of eye development when retinal neurogenesis is initiated.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping