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Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus

Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication includin...

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Autores principales: Cipriani, Valentina, Silva, Raquel S., Arno, Gavin, Pontikos, Nikolas, Kalhoro, Ambreen, Valeina, Sandra, Inashkina, Inna, Audere, Mareta, Rutka, Katrina, Puech, Bernard, Michaelides, Michel, van Heyningen, Veronica, Lace, Baiba, Webster, Andrew R., Moore, Anthony T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548758/
https://www.ncbi.nlm.nih.gov/pubmed/28790370
http://dx.doi.org/10.1038/s41598-017-06387-6
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author Cipriani, Valentina
Silva, Raquel S.
Arno, Gavin
Pontikos, Nikolas
Kalhoro, Ambreen
Valeina, Sandra
Inashkina, Inna
Audere, Mareta
Rutka, Katrina
Puech, Bernard
Michaelides, Michel
van Heyningen, Veronica
Lace, Baiba
Webster, Andrew R.
Moore, Anthony T.
author_facet Cipriani, Valentina
Silva, Raquel S.
Arno, Gavin
Pontikos, Nikolas
Kalhoro, Ambreen
Valeina, Sandra
Inashkina, Inna
Audere, Mareta
Rutka, Katrina
Puech, Bernard
Michaelides, Michel
van Heyningen, Veronica
Lace, Baiba
Webster, Andrew R.
Moore, Anthony T.
author_sort Cipriani, Valentina
collection PubMed
description Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development.
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spelling pubmed-55487582017-08-09 Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus Cipriani, Valentina Silva, Raquel S. Arno, Gavin Pontikos, Nikolas Kalhoro, Ambreen Valeina, Sandra Inashkina, Inna Audere, Mareta Rutka, Katrina Puech, Bernard Michaelides, Michel van Heyningen, Veronica Lace, Baiba Webster, Andrew R. Moore, Anthony T. Sci Rep Article Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development. Nature Publishing Group UK 2017-08-08 /pmc/articles/PMC5548758/ /pubmed/28790370 http://dx.doi.org/10.1038/s41598-017-06387-6 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Cipriani, Valentina
Silva, Raquel S.
Arno, Gavin
Pontikos, Nikolas
Kalhoro, Ambreen
Valeina, Sandra
Inashkina, Inna
Audere, Mareta
Rutka, Katrina
Puech, Bernard
Michaelides, Michel
van Heyningen, Veronica
Lace, Baiba
Webster, Andrew R.
Moore, Anthony T.
Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
title Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
title_full Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
title_fullStr Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
title_full_unstemmed Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
title_short Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
title_sort duplication events downstream of irx1 cause north carolina macular dystrophy at the mcdr3 locus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548758/
https://www.ncbi.nlm.nih.gov/pubmed/28790370
http://dx.doi.org/10.1038/s41598-017-06387-6
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