Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
| Autor: | Michel Michaelides, Valentina Cipriani, Sandra Valeina, Nikolas Pontikos, Andrew R. Webster, Gavin Arno, Bernard Puech, Inna Inashkina, Veronica van Heyningen, Raquel S. Silva, Mareta Audere, Baiba Lace, Anthony T. Moore, Katrina Rutka, Ambreen Kalhoro |
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| Rok vydání: | 2017 |
| Předmět: |
Male
Gene Expression Neurodegenerative Eye Macular Degeneration ADAMTS Proteins Gene duplication Chromosome Duplication 2.1 Biological and endogenous factors Aetiology Tomography Corneal Dystrophies Hereditary Genetics Hereditary Chromosomes Human Pair 5 Medicine Chromosomes Human Pair 6 Female Pair 6 Pair 5 NORTH CAROLINA MACULAR DYSTROPHY Sequence Analysis Tomography Optical Coherence Human IRX1 Adult medicine.medical_specialty Corneal Dystrophies Science Genomics Locus (genetics) Biology Article Retina Chromosomes Fetus Molecular genetics medicine Humans Family Eye Proteins Gene Eye Disease and Disorders of Vision Homeodomain Proteins Base Sequence Haplotype Human Genome Sequence Analysis DNA DNA Haplotypes Optical Coherence Genetic Loci Transcription Factors |
| Zdroj: | Scientific reports, vol 7, iss 1 Scientific Reports, Vol 7, Iss 1, Pp 1-9 (2017) Scientific Reports |
| Popis: | Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been assigned by linkage to two loci, MCDR1 on chromosome 6q16 and MCDR3 on chromosome 5p15-p13. Recently, noncoding variants upstream ofPRDM13and a large duplication includingIRX1have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream ofIRX1and upstream ofADAMTS16.One duplication of 43 kb was identified in nine NCMD families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. 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 ofIRX1andADAMTS16in human fetal retina, withIRX1preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD at the MCDR3 locus and provide insights into the genetic pathways involved in human macular development.Abbreviations listaCGHarray comparative genomic hybridizationCNVCopy number variantIBDIdentical-by-descentiPSCInduced pluripotent stem cellDHSDNase hypersensitive siteHHHomozygosity HaplotypeMCDRMacular dystrophy regionNCMDNorth Carolina macular dystrophyPCRPolymerase chain reactionRCHHRegion with a Conserved Homozygosity HaplotypeSNPSingle-nucleotide polymorphismSNVSingle nucleotide variantSVStructural variantWGSWhole-genome sequencing |
| Databáze: | OpenAIRE |
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