The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy
Por:
Wissinger B, Baumann B, Buena-Atienza E, Ravesh Z, Cideciyan AV, Stingl K, Audo I, Meunier I, Bocquet B, Traboulsi EI, Hardcastle AJ, Gardner JC, Michaelides M, Branham KE, Rosenberg T, Andreasson S, Dollfus H, Birch D, Vincent AL, Martorell-Sampol L, Català-Mora J, Kellner U, Rüther K, Lorenz B, Preising MN, Manfredini E, Zarate YA, Vijzelaar R, Zrenner E, Jacobson SG and Kohl S
Publicada:
5 jul 2022
Categoría:
Multidisciplinary
Resumen:
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.
Filiaciones:
Wissinger B:
Molecular Genetics Laboratory, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany
Baumann B:
Molecular Genetics Laboratory, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany
Buena-Atienza E:
Molecular Genetics Laboratory, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany
Ravesh Z:
Molecular Genetics Laboratory, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany
Cideciyan AV:
Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
Stingl K:
University Eye Hospital, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany
Center for Rare Eye Diseases, University of Tuebingen, 72076 Tuebingen, Germany
Audo I:
Sorbonne Université, INSERM, CNRS, Institut de la Vision, 75012 Paris, France
Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC 1423, 75571 Paris, France
Meunier I:
National Reference Centre for Inherited Sensory Diseases, Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, 34091 Montpellier, France
Bocquet B:
National Reference Centre for Inherited Sensory Diseases, Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, 34091 Montpellier, France
Traboulsi EI:
Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195
Hardcastle AJ:
Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom
Gardner JC:
Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom
Michaelides M:
Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom
Moorfields Eye Hospital, University College London, London EC1V 2PD, United Kingdom
Branham KE:
Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI 48109
Rosenberg T:
Department of Ophthalmology, Kennedy Center, Rigshospitalet, 2600 Glostrup, Denmark
Andreasson S:
Department of Ophthalmology, University of Lund, 22362 Lund, Sweden
Dollfus H:
Centre de référence pour les Affections Rares en Génétique Ophtalmologique, Filière de santé maladies rares SENSGENE, Institut de Génétique médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
Birch D:
Retina Foundation of the Southwest, Dallas, TX 75231
Vincent AL:
Department of Ophthalmology, National Eye Centre, Faculty of Medical and Health Science, University of Auckland, Auckland 1023, New Zealand
Martorell-Sampol L:
Molecular Genetics Department, Hopital Sant Joan de Déu Barcelona, 08950 Esplugues de Llobregat, Spain
Català-Mora J:
Unitat de Distròfies Hereditàries de Retina, Hospital Sant Joan de Déu Barcelona, 08950 Esplugues de Llobregat, Spain
Kellner U:
Zentrum für Seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum Siegburg, 53721 Siegburg, Germany
Rüther K:
Augenarztpraxis, 10117 Berlin, Germany
Lorenz B:
Department of Ophthalmology, Justus-Liebig-University Giessen, 35385 Giessen, Germany
Universitäts-Augenklinik, University of Bonn, 53127 Bonn, Germany
Preising MN:
Department of Ophthalmology, Justus-Liebig-University Giessen, 35385 Giessen, Germany
Manfredini E:
Dipartimento di Medicina di Laboratorio, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy
Zarate YA:
Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72202
Vijzelaar R:
MRC Holland b.v., Amsterdam 1057 DL, The Netherlands
Zrenner E:
Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany
Jacobson SG:
Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
Kohl S:
Molecular Genetics Laboratory, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany
Green Published
|