title: 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.
authors: Neuroscience Research Center and Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors: Noor M
authors: NM
authors: Ghiasvand
authors: Dellaney D
authors: DD
authors: Rudolph
authors: Mohammad
authors: M
authors: Mashayekhi
authors: Joseph A
authors: JA
authors: Brzezinski
authors: Daniel
authors: D
authors: Goldman
authors: Tom
authors: T
authors: Glaser
mesh_terms: D000293:Adolescent; D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002675:Child, Preschool; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D019295:Computational Biology / Q000379:methods; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004622:Embryo, Mammalian; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005192:Family Health; D005260:Female; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D007492:Iran / Q000208:ethnology; D008164:Luminescent Proteins / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008875:Middle Aged; D055495:Neurogenesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012160:Retina / Q000166:cytology* / Q000196:embryology; D012163:Retinal Detachment / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion / Q000235:genetics*; D013477:Superior Colliculi / Q000473:pathology; D015027:Zebrafish / Q000254:growth & development
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008164:Luminescent Proteins; C456975:ATOH7 protein, human