| Autor: |
Conte I; Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy;, Hadfield KD; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom;, Barbato S; Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy;, Carrella S; Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy;, Pizzo M; Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy;, Bhat RS; Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy;, Carissimo A; Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy;, Karali M; Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy;, Porter LF; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, United Kingdom;, Urquhart J; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, United Kingdom;, Hateley S; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom;, O'Sullivan J; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom;, Manson FD; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom;, Neuhauss SC; Institute of Molecular Life Sciences, University of Zurich, CH-8057 Zurich, Switzerland;, Banfi S; Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy; Medical Genetics, Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy; European Retinal Dystrophy Consortium; banfi@tigem.it graeme.black@manchester.ac.uk., Black GC; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, United Kingdom; European Retinal Dystrophy Consortium; United Kingdom Inherited Retinal Disease Consortium, Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, United Kingdom banfi@tigem.it graeme.black@manchester.ac.uk. |
| Abstrakt: |
Ocular developmental disorders, including the group classified as microphthalmia, anophthalmia, and coloboma (MAC) and inherited retinal dystrophies, collectively represent leading causes of hereditary blindness. Characterized by extreme genetic and clinical heterogeneity, the separate groups share many common genetic causes, in particular relating to pathways controlling retinal and retinal pigment epithelial maintenance. To understand these shared pathways and delineate the overlap between these groups, we investigated the genetic cause of an autosomal dominantly inherited condition of retinal dystrophy and bilateral coloboma, present in varying degrees in a large, five-generation family. By linkage analysis and exome sequencing, we identified a previously undescribed heterozygous mutation, n.37 C > T, in the seed region of microRNA-204 (miR-204), which segregates with the disease in all affected individuals. We demonstrated that this mutation determines significant alterations of miR-204 targeting capabilities via in vitro assays, including transcriptome analysis. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family, including photoreceptor alterations with reduced numbers of both cones and rods as a result of increased apoptosis, thereby confirming the pathogenic effect of the n.37 C > T mutation. Finally, knockdown assays in medaka fish demonstrated that miR-204 is necessary for normal photoreceptor function. Overall, these data highlight the importance of miR-204 in the regulation of ocular development and maintenance and provide the first evidence, to our knowledge, of its contribution to eye disease, likely through a gain-of-function mechanism. |
