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Autor
Agemy, Steven 1 Balikova, Irina 1 Bergen, Arthur A 1 Boon, Camiel J F 1 Cicekdal, Munevver Burcu 1 D'haene, Eva 1 De Baere, Elfride 1 De Zaeytijd, Julie 1 Gómez-Skarmeta, José Luis 1 Inglehearn, Chris F 1 Kousal, Bohdan 1 Leroy, Bart P 1 Liskova, Petra 1 Martinez-Morales, Juan R 1 Rey, Alfredo Dueñas 1 Rivolta, Carlo 1 Rosseel, Toon 1 Shaya, Fadi S 1 Small, Kent W 1 Soriano, Víctor López 1
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Bartiméus Diagnostic Center for Compl... 1 Center for Medical Genetics Antwerp U... 1 Center for Medical Genetics Ghent Uni... 1 Centro Andaluz de Biología del Desarr... 1 Department of Biomedical Molecular Bi... 1 Department of Biomolecular Medicine G... 1 Department of Genetics and Genome Bio... 1 Department of Head and Skin Ghent Uni... 1 Department of Human Genetics Amsterda... 1 Department of Ophthalmology 1st Facul... 1 Department of Ophthalmology Amsterdam... 1 Department of Ophthalmology Ghent Uni... 1 Department of Ophthalmology Leiden Un... 1 Department of Ophthalmology SUNY Down... 1 Department of Ophthalmology Universit... 1 Department of Ophthalmology Universit... 1 Department of Paediatrics and Inherit... 1 Division of Molecular Medicine Leeds ... 1 Division of Ophthalmology and Center ... 1 Institute of Molecular and Clinical O... 1
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Autor
Agemy, Steven 1 Balikova, Irina 1 Bergen, Arthur A 1 Boon, Camiel J F 1 Cicekdal, Munevver Burcu 1 D'haene, Eva 1 De Baere, Elfride 1 De Zaeytijd, Julie 1 Gómez-Skarmeta, José Luis 1 Inglehearn, Chris F 1 Kousal, Bohdan 1 Leroy, Bart P 1 Liskova, Petra 1 Martinez-Morales, Juan R 1 Rey, Alfredo Dueñas 1 Rivolta, Carlo 1 Rosseel, Toon 1 Shaya, Fadi S 1 Small, Kent W 1 Soriano, Víctor López 1
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Pracoviště
Bartiméus Diagnostic Center for Compl... 1 Center for Medical Genetics Antwerp U... 1 Center for Medical Genetics Ghent Uni... 1 Centro Andaluz de Biología del Desarr... 1 Department of Biomedical Molecular Bi... 1 Department of Biomolecular Medicine G... 1 Department of Genetics and Genome Bio... 1 Department of Head and Skin Ghent Uni... 1 Department of Human Genetics Amsterda... 1 Department of Ophthalmology 1st Facul... 1 Department of Ophthalmology Amsterdam... 1 Department of Ophthalmology Ghent Uni... 1 Department of Ophthalmology Leiden Un... 1 Department of Ophthalmology SUNY Down... 1 Department of Ophthalmology Universit... 1 Department of Ophthalmology Universit... 1 Department of Paediatrics and Inherit... 1 Division of Molecular Medicine Leeds ... 1 Division of Ophthalmology and Center ... 1 Institute of Molecular and Clinical O... 1
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Free Medical Journals od 1949 do Před 6 měsíci
PubMed Central od 1949 do Před 6 měsíci
Europe PubMed Central od 1949 do Před 6 měsíci
Open Access Digital Library od 2005-01-01
Elsevier Open Access Journals od 1997-06-01
Elsevier Open Archive Journals od 1997 do Před 6 měsíci
PubMed
36243009
DOI
10.1016/j.ajhg.2022.09.013
Knihovny.cz E-zdroje
North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMD-associated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.
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