Abstract
Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families—all from the United States—showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no “region of overlap” among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.
| Original language | English |
|---|---|
| Article number | e2115538119 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 119 |
| Issue number | 27 |
| DOIs | |
| State | Published - Jul 5 2022 |
Bibliographical note
Publisher Copyright:Copyright © 2022 the Author(s).
Funding
We thank all families for participation in this study and Miss Sabine Tippmann and the late Miss Monika Papke for technical assistance in the initial phase of this project. We also want to thank the late Christian Hamel for the excellent and amicable cooperation before his much-too-early passing. The work was supported by a grant of the German Research Council (Wi1189/12-1 to B.W.), the Blue Cone Monochromacy Family Foundation, and Dr. Renata Sarno as well as in parts by funds of the UK Medical Research Council (to A.J.H.) and a grant from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (to M.M.). Patient clinical care and recruitment in Tuebingen was supported by the Tistou and Charlotte Kerstan Foundation. The Parisian group (I.A.) was supported by LabEx LifeSenses, IHU FOReSIGHT, and a Fondation Fighting Blindness grant (BR-GE-0619-0761-INSERM). DNA samples collected by the Parisian group originate from NeuroSensCol, a biobank for research in neuroscience (Principal Investigator: J. A. Sahel; co-Principal Investigator: I.A., partner with Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, INSERM and CNRS). Katarina Stingl, Isabelle Audo, Isabelle Meunier, Michel Michaelides, Helene Dollfus, Birgit Lorenz, Markus Preising, Eberhart Zrenner, and Susanne Kohl are members of ERN-EYE (European Reference Network for Rare Eye Diseases). ACKNOWLEDGMENTS. We thank all families for participation in this study and Miss Sabine Tippmann and the late Miss Monika Papke for technical assistance in the initial phase of this project. We also want to thank the late Christian Hamel for the excellent and amicable cooperation before his much-too-early passing. The work was supported by a grant of the German Research Council (Wi1189/12-1 to B.W.), the Blue Cone Monochromacy Family Foundation, and Dr. Renata Sarno as well as in parts by funds of the UK Medical Research Council (to A.J.H.) and a grant from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (to M.M.). Patient clinical care and recruitment in Tuebin-gen was supported by the Tistou and Charlotte Kerstan Foundation. The Parisian group (I.A.) was supported by LabEx LifeSenses, IHU FOReSIGHT, and a Fonda-tion Fighting Blindness grant (BR-GE-0619-0761-INSERM). DNA samples collected by the Parisian group originate from NeuroSensCol, a biobank for research in neuroscience (Principal Investigator: J. A. Sahel; co-Principal Investigator: I.A., partner with Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, INSERM and CNRS). Katarina Stingl, Isabelle Audo, Isabelle Meunier, Michel Michaelides, Helene Dollfus, Birgit Lorenz, Markus Preising, Eberhart Zrenner, and Susanne Kohl are members of ERN-EYE (European Reference Network for Rare Eye Diseases).
| Funders | Funder number |
|---|---|
| Blue Cone Monochromacy Family Foundation | |
| LabEx LifeSenses | |
| NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research | |
| Foundation Fighting Blindness | BR-GE-0619-0761-INSERM |
| UK Medical Research Council, Engineering and Physical Sciences Research Council | |
| UCL Institute of Ophthalmology, University College London | |
| Deutsche Forschungsgemeinschaft | Wi1189/12-1 |
| CNRS Centre National de la Recherche Scientifique | |
| Moorfields Eye Hospital NHS Foundation Trust | |
| Tistou and Charlotte Kerstan Stiftung |
Keywords
- BCM
- gene conversion
- human visual pigment genes
- locus control region
- opsin gene deletion
ASJC Scopus subject areas
- General
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