Biallelic Mutations in the Autophagy Regulator DRAM2 Cause Retinal Dystrophy with Early Macular Involvement Mohammed E. El-Asrag, Panagiotis I. Sergouniotis,

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Biallelic Mutations in the Autophagy Regulator DRAM2 Cause Retinal Dystrophy with Early Macular Involvement Mohammed E. El-Asrag, Panagiotis I. Sergouniotis, Martin McKibbin, Vincent Plagnol, Eamonn Sheridan, Naushin Waseem, Zakia Abdelhamed, Declan McKeefry, Kristof Van Schil, James A. Poulter Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Simon Ramsden, Forbes Manson, Alison Hardcastle, Michel Michaelides, Michael Cheetham, Gavin Arno, Niclas Thomas, Shomi Bhattacharya, Tony Moore, Andrea Nemeth, Susan Downes, Stefano Lise, Emma Lord, Colin A. Johnson, Ian M. Carr, Bart P. Leroy, Elfride De Baere, Chris F. Inglehearn, Andrew R. Webster, Carmel Toomes, Manir Ali Mohammed E. El-Asrag, Panagiotis I. Sergouniotis, Martin McKibbin, Vincent Plagnol, Eamonn Sheridan, Naushin Waseem, Zakia Abdelhamed, Declan McKeefry, Kristof Van Schil, James A. Poulter Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Simon Ramsden, Forbes Manson, Alison Hardcastle, Michel Michaelides, Michael Cheetham, Gavin Arno, Niclas Thomas, Shomi Bhattacharya, Tony Moore, Andrea Nemeth, Susan Downes, Stefano Lise, Emma Lord, Colin A. Johnson, Ian M. Carr, Bart P. Leroy, Elfride De Baere, Chris F. Inglehearn, Andrew R. Webster, Carmel Toomes, Manir Ali The American Journal of Human Genetics Volume 96, Issue 6, Pages 948-954 (June 2015) DOI: 10.1016/j.ajhg.2015.04.006 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Features of Individuals from Family ES1 with Retinal Dystrophy and Early Maculopathy Caused by Recessive DRAM2 Mutations Color fundus photograph (A), fundus autofluorescence (C), infra-red reflectance (E), and OCT (F) images from the right eye of subject IV.9 at 25 years. Corresponding images from an unaffected individual are provided for comparison (B, D, G, and H). Macular atrophy with white dots at its temporal edge are observed on fundus photography. On autofluorescence imaging, there is a central area of reduced autofluorescence surrounded by a hyperautofluorescent ring. On OCT imaging, there is significant thinning in the foveal region consistent with photoreceptor loss. A composite color photograph from the left eye of case III.1, at the age of 48, is also shown (I). This reveals macular atrophy, mid-peripheral bone-spicule pigmentation, and attenuated retinal vessels. On the infra-red reflectance images, the horizontal green lines indicate the position and direction of the corresponding OCT scan. The scale bars represent 200 μm. The American Journal of Human Genetics 2015 96, 948-954DOI: (10.1016/j.ajhg.2015.04.006) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigrees of Families and Case Subjects Reported in This Study and DRAM2 Mutation Segregation Data Affected individuals are shaded black. The maternal grandmother of individual gc17004 has age-related macular degeneration in her 90s (shaded gray). The genotypes for all tested family members are shown below each individual, with M representing the mutant allele and + representing the wild-type allele. The American Journal of Human Genetics 2015 96, 948-954DOI: (10.1016/j.ajhg.2015.04.006) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 Variants in DRAM2 Cause Retinal Dystrophy (A) Schematic representation of the DRAM2 genomic structure and major transcript (GenBank: NM_178454.4) showing the location and sequence traces of the seven disease-causing variants identified in this study. (B) Schematic diagram of DRAM2 showing the location of the affected amino acids within the protein domains. The American Journal of Human Genetics 2015 96, 948-954DOI: (10.1016/j.ajhg.2015.04.006) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 4 Localization of DRAM2 to the Photoreceptor Inner Segments and Retina Pigment Epithelium Radial 6 μm cryosections of mature mouse retina (P30) were labeled with anti-DRAM2 (M-12, Santa Cruz Biotechnology) and anti-Rhodopsin (Sigma-Aldrich) followed by the secondary antibody Alexa Fluor 568-conjugated donkey anti-goat immunoglobulin (red) (Molecular Probes Incorporation) and Alexa Fluor 488-conjugated chicken anti-rabbit immunoglobulin (green) (Molecular Probes Incorporation), respectively, and the nuclei were counterstained with DAPI (Vector Laboratories). An independent section stained with both secondary antibodies only and another with peptide (Santa Cruz Biotechnology, sc-241077-P)-competition against the DRAM2 primary antibody served as negative controls in the experiment. Immunofluorescence was analyzed with an Eclipse TE2000-E inverted confocal microscope (Nikon Instruments) and shows localization of DRAM2 to the inner segment of the photoreceptor layer (PIS) and the retinal pigment epithelium (RPE). Rhodopsin localizes to the outer segment of the photoreceptor layer (POS). The other layers are the outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), and the ganglion cell layer (GCL). Scale bar represents 50 μm. The American Journal of Human Genetics 2015 96, 948-954DOI: (10.1016/j.ajhg.2015.04.006) Copyright © 2015 The American Society of Human Genetics Terms and Conditions