Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease

Noor M. Ghiasvand, Dellaney D. Rudolph, Mohammad Mashayekhi, Joseph A. Brzezinski, Daniel Goldman, Thomas M Glaser

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)578-588
Number of pages11
JournalNature Neuroscience
Volume14
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Ghiasvand, N. M., Rudolph, D. D., Mashayekhi, M., Brzezinski, J. A., Goldman, D., & Glaser, T. M. (2011). Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease. Nature Neuroscience, 14(5), 578-588. https://doi.org/10.1038/nn.2798