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Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders |
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| Authors: | Alberta AHJ Thiadens Anneke I den Hollander Susanne Roosing Renate C Zekveld-Vroon Elfride De Baere Mary J van Schooneveld Janneke JC van Lith-Verhoeven Norka van Moll-Ramirez L Ingeborgh van den Born Frans PM Cremers Caroline CW Klaver |
| Institution: | 1 Department of Ophthalmology, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands 2 Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands 3 Department of Ophthalmology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands 4 Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, PO Box 9102, 6500 HC Nijmegen, The Netherlands 5 Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen, PO Box 9102, 6500 HC Nijmegen, The Netherlands 6 Centre for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium 7 McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, QC H3H 1P3, Canada 8 Department of Ophthalmogenetics, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands 9 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany 10 Division of Clinical Neurosciences, University of Southampton, Southampton SO16 6YD, UK 11 Sensis Grave, 5361 HK Grave, The Netherlands 12 Department of Ophthalmology, Ghent University Hospital, B-9000 Ghent, Belgium 13 The Rotterdam Eye Hospital, PO Box 7000, 3000 LM Rotterdam, The Netherlands 14 Department of Epidemiology, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands |
| Abstract: | Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone α subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5′-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes. |
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