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

Abstract 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...

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Autores principales:	Valentina Cipriani, Raquel S. Silva, Gavin Arno, Nikolas Pontikos, Ambreen Kalhoro, Sandra Valeina, Inna Inashkina, Mareta Audere, Katrina Rutka, Bernard Puech, Michel Michaelides, Veronica van Heyningen, Baiba Lace, Andrew R. Webster, Anthony T. Moore
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Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2d372407022b447ebe6a08634c10139b
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spelling	oai:doaj.org-article:2d372407022b447ebe6a08634c10139b2021-12-02T11:52:44ZDuplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus10.1038/s41598-017-06387-62045-2322https://doaj.org/article/2d372407022b447ebe6a08634c10139b2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06387-6https://doaj.org/toc/2045-2322Abstract 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.Valentina CiprianiRaquel S. SilvaGavin ArnoNikolas PontikosAmbreen KalhoroSandra ValeinaInna InashkinaMareta AudereKatrina RutkaBernard PuechMichel MichaelidesVeronica van HeyningenBaiba LaceAndrew R. WebsterAnthony T. MooreNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Valentina Cipriani Raquel S. Silva Gavin Arno Nikolas Pontikos Ambreen Kalhoro Sandra Valeina Inna Inashkina Mareta Audere Katrina Rutka Bernard Puech Michel Michaelides Veronica van Heyningen Baiba Lace Andrew R. Webster Anthony T. Moore Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
description	Abstract 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.
format	article
author	Valentina Cipriani Raquel S. Silva Gavin Arno Nikolas Pontikos Ambreen Kalhoro Sandra Valeina Inna Inashkina Mareta Audere Katrina Rutka Bernard Puech Michel Michaelides Veronica van Heyningen Baiba Lace Andrew R. Webster Anthony T. Moore
author_facet	Valentina Cipriani Raquel S. Silva Gavin Arno Nikolas Pontikos Ambreen Kalhoro Sandra Valeina Inna Inashkina Mareta Audere Katrina Rutka Bernard Puech Michel Michaelides Veronica van Heyningen Baiba Lace Andrew R. Webster Anthony T. Moore
author_sort	Valentina Cipriani
title	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_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_sort	duplication events downstream of irx1 cause north carolina macular dystrophy at the mcdr3 locus
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2d372407022b447ebe6a08634c10139b
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Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus

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