title: Biallelic mutations in the autophagy regulator DRAM2 cause retinal dystrophy with early macular involvement.
abstract: Retinal dystrophies are an overlapping group of genetically heterogeneous conditions resulting from mutations in more than 250 genes. Here we describe five families affected by an adult-onset retinal dystrophy with early macular involvement and associated central visual loss in the third or fourth decade of life. Affected individuals were found to harbor disease-causing variants in DRAM2 (DNA-damage regulated autophagy modulator protein 2). Homozygosity mapping and exome sequencing in a large, consanguineous British family of Pakistani origin revealed a homozygous frameshift variant (c.140delG [p.Gly47Valfs(∗)3]) in nine affected family members. Sanger sequencing of DRAM2 in 322 unrelated probands with retinal dystrophy revealed one European subject with compound heterozygous DRAM2 changes (c.494G>A [p.Trp165(∗)] and c.131G>A [p.Ser44Asn]). Inspection of previously generated exome sequencing data in unsolved retinal dystrophy cases identified a homozygous variant in an individual of Indian origin (c.64_66del [p.Ala22del]). Independently, a gene-based case-control association study was conducted via an exome sequencing dataset of 18 phenotypically similar case subjects and 1,917 control subjects. Using a recessive model and a binomial test for rare, presumed biallelic, variants, we found DRAM2 to be the most statistically enriched gene; one subject was a homozygote (c.362A>T [p.His121Leu]) and another a compound heterozygote (c.79T>C [p.Tyr27His] and c.217_225del [p.Val73_Tyr75del]). DRAM2 encodes a transmembrane lysosomal protein thought to play a role in the initiation of autophagy. Immunohistochemical analysis showed DRAM2 localization to photoreceptor inner segments and to the apical surface of retinal pigment epithelial cells where it might be involved in the process of photoreceptor renewal and recycling to preserve visual function.
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK; Department of Zoology, Faculty of Science, Benha University, 13511 Benha, Egypt.
authors.forename: Mohammed E
authors.initials: ME
authors.lastname: El-Asrag
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.affiliation: Department of Ophthalmology, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.affiliation: UCL Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Naushin
authors.initials: N
authors.lastname: Waseem
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Zakia
authors.initials: Z
authors.lastname: Abdelhamed
authors.affiliation: Bradford School of Optometry and Visual Science, University of Bradford, Bradford BD7 1DP, UK.
authors.forename: Declan
authors.initials: D
authors.lastname: McKeefry
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Schil
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Poulter
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Ophthalmology, Ghent University Hospital, 9000 Ghent, Belgium; Division of Ophthalmology, The Children's Hospital of Philadelphia, PA 19104, USA.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK. Electronic address: c.toomes@leeds.ac.uk.
authors.forename: Carmel
authors.initials: C
authors.lastname: Toomes
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK. Electronic address: m.ali@leeds.ac.uk.
authors.forename: Manir
authors.initials: M
authors.lastname: Ali
mesh_terms: D000328:Adult; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010154:Pakistan / Q000208:ethnology; D010375:Pedigree; D058499:Retinal Dystrophies / Q000235:genetics* / Q000473:pathology*; D017422:Sequence Analysis, DNA; D006113:United Kingdom
chemical_list: C544299:DRAM2 protein, human; D008565:Membrane Proteins