title: De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy.
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.
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Buena-Atienza
authors.affiliation: Sankt Gertrauden-Krankenhaus, Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rüther
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Baumann
authors.affiliation: Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Bergholz
authors.affiliation: Retina Foundation of the Southwest, Tom and Dorothy Anderson Vision Research Center, Texas, USA.
authors.forename: David
authors.initials: D
authors.lastname: Birch
authors.affiliation: Department of Ophthalmology &Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.affiliation: Centre de Référence pour les Affections Rares en Génétique Ophtalmologique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Dollfus
authors.affiliation: National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Greally
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Gustavsson
authors.affiliation: Genetic Sensory Diseases - Hopital Gui de Chauliac, Centre Hospitalier Universitaire, Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.affiliation: Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.affiliation: Department of Ophthalmology &Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Plomp
authors.affiliation: Department of Ophthalmology, University Medical Centre Groningen, University of Groningen, The Netherlands.
authors.forename: Jan Willem R
authors.initials: JW
authors.lastname: Pott
authors.affiliation: Genetic Health Services Victoria, Monash Medical Centre, Parkville, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Rose
authors.affiliation: National Eye Clinic for the Visually Impaired, Kennedy Center, Glostrup, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
authors.affiliation: Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Zornitza
authors.initials: Z
authors.lastname: Stark
authors.affiliation: Department of Medical Genetics, University Medical Centre Groningen, University of Groningen, The Netherlands.
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.affiliation: Department of Ophthalmic Genetics, Casey Eye Institute, Portland, OR, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Weleber
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Ditta
authors.initials: D
authors.lastname: Zobor
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Weisschuh
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
mesh_terms: D003117:Color Vision Defects / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D004596:Electroretinography; D005091:Exons; D005260:Female; D005785:Gene Conversion; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D008297:Male; D005810:Multigene Family; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017299:Rod Opsins / Q000235:genetics*
chemical_list: D017299:Rod Opsins; C095855:long-wavelength opsin; C095854:middle-wavelength opsin