Deletion of a remote enhancer near atoh7 disrupts retinal neurogenesis, causing ncrna disease

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through

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Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DELETION UPSTREAM OF _MAB21L2_ HIGHLIGHTS THE IMPORTANCE OF EVOLUTIONARILY CONSERVED NON-CODING SEQUENCES FOR

EYE DEVELOPMENT Article Open access 26 October 2024 IHH ENHANCER VARIANT WITHIN NEIGHBORING NHEJ1 INTRON CAUSES MICROPHTHALMIA ANOPHTHALMIA AND COLOBOMA Article Open access 14 August 2023

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collaborative project, A. Aledavood for logistical support and encouragement, H. Parmar, J. Trobe and E. Oliver for help interpreting MRI studies, L. Prasov for assistance with mouse tissue

cDNAs and retinal dissections, J. Johnson for pBGn-Cherry plasmid DNA, N. Brown for Math5-GFP transgenic mice, I. Masai for_ath5:GFP_ transgenic fish, M. Pihalja and M. Chiang for flow

cytometry advice, S. Philips and T. Masud for screening candidate genes, S. Dagenais and R. Lyons for SNP genotyping analysis, S. Barolo, N. Brown, L. Prasov, C. Chou, M. Meisler and B. Link

for helpful suggestions, and to T. Saunders, M. van Keuren and the University of Michigan transgenic animal, flow cytometry and DNA sequencing cores for technical support. We are profoundly

grateful to NCRNA family members for their involvement and dedication to this study over many years. The research was funded by grants from the Glaucoma Foundation and the University of

Michigan Center for Genetics in Health and Medicine to T.G., and from the US National Institutes of Health to T.G. (EY14259), D.G. (EY18132) and J.A.B. (T32 EY13934). AUTHOR INFORMATION

Author notes * Joseph A Brzezinski IV Present address: Present address:Department of Biological Structure, University of Washington,Seattle,Washington, USA., AUTHORS AND AFFILIATIONS *

Neuroscience Research Center and Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Noor M Ghiasvand * Department of Biology,

Grand Valley State University, Allendale, Michigan, USA Noor M Ghiasvand * Departments of Human Genetics and Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Dellaney D

Rudolph, Joseph A Brzezinski IV & Tom Glaser * Ophthalmology Ward, Emam Ali Hospital, Bojnourd, North Khorasan, Iran Mohammad Mashayekhi * Department of Biochemistry, Molecular and

Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA Daniel Goldman Authors * Noor M Ghiasvand View author publications You can also search for this author

inPubMed Google Scholar * Dellaney D Rudolph View author publications You can also search for this author inPubMed Google Scholar * Mohammad Mashayekhi View author publications You can also

search for this author inPubMed Google Scholar * Joseph A Brzezinski IV View author publications You can also search for this author inPubMed Google Scholar * Daniel Goldman View author

publications You can also search for this author inPubMed Google Scholar * Tom Glaser View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS

N.M.G. and M.M. collected clinical data. N.M.G., D.D.R., J.A.B. and T.G. performed genomic and functional experiments. D.G. developed and bred transgenic fish. N.M.G., D.D.R., J.A.B., D.G.

and T.G. analyzed data and wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Tom Glaser. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial

interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–10, Supplementary Tables 1–3 and Supplementary Note (PDF 905 kb) RIGHTS AND PERMISSIONS Reprints

and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ghiasvand, N., Rudolph, D., Mashayekhi, M. _et al._ Deletion of a remote enhancer near _ATOH7_ disrupts retinal neurogenesis, causing

NCRNA disease. _Nat Neurosci_ 14, 578–586 (2011). https://doi.org/10.1038/nn.2798 Download citation * Received: 04 January 2011 * Accepted: 07 March 2011 * Published: 27 March 2011 * Issue

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