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Sci Rep. 2016 Jun 24;6:28253. doi: 10.1038/srep28253.

De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy.

Author information

1
Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.
2
Sankt Gertrauden-Krankenhaus, Berlin, Germany.
3
Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
4
Retina Foundation of the Southwest, Tom and Dorothy Anderson Vision Research Center, Texas, USA.
5
Department of Ophthalmology &Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
6
Centre de Référence pour les Affections Rares en Génétique Ophtalmologique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
7
National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin, Ireland.
8
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
9
Genetic Sensory Diseases - Hopital Gui de Chauliac, Centre Hospitalier Universitaire, Montpellier, France.
10
Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA.
11
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
12
Department of Ophthalmology, University Medical Centre Groningen, University of Groningen, The Netherlands.
13
Genetic Health Services Victoria, Monash Medical Centre, Parkville, Australia.
14
National Eye Clinic for the Visually Impaired, Kennedy Center, Glostrup, Denmark.
15
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
16
Department of Medical Genetics, University Medical Centre Groningen, University of Groningen, The Netherlands.
17
Department of Ophthalmic Genetics, Casey Eye Institute, Portland, OR, USA.

Abstract

X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay. Nine haplotypes resulted in aberrant splicing of ≥20% of transcripts including the known pathogenic haplotypes (i.e. 'LIAVA', 'LVAVA') with absent or minute amounts of correctly spliced transcripts, respectively. De novo formation of the 'LIAVA' haplotype derived from an ancestral less deleterious 'LIAVS' haplotype was observed in one family with strikingly different phenotypes among affected family members. We could establish intrachromosomal gene conversion in the male germline as underlying mechanism. Gene conversion in the OPN1LW/OPN1MW genes has been postulated, however, we are first to demonstrate a de novo gene conversion within the lineage of a pedigree.

PMID:
27339364
PMCID:
PMC4919619
DOI:
10.1038/srep28253
[Indexed for MEDLINE]
Free PMC Article

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