2. Academic Validation
  3. Biallelic mutations in the autophagy regulator DRAM2 cause retinal dystrophy with early macular involvement

Biallelic mutations in the autophagy regulator DRAM2 cause retinal dystrophy with early macular involvement

  • Am J Hum Genet. 2015 Jun 4;96(6):948-54. doi: 10.1016/j.ajhg.2015.04.006.
Mohammed E El-Asrag 1,  Panagiotis I Sergouniotis 2,  Martin McKibbin 3,  Vincent Plagnol 4,  Eamonn Sheridan 5,  Naushin Waseem 6,  Zakia Abdelhamed 7,  Declan McKeefry 8,  Kristof Van Schil 9,  James A Poulter 7,  UK Inherited Retinal Disease Consortium,  Colin A Johnson 7,  Ian M Carr 7,  Bart P Leroy 10,  Elfride De Baere 9,  Chris F Inglehearn 7,  Andrew R Webster 11,  Carmel Toomes 12,  Manir Ali 13
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Ophthalmology, St. James's University Hospital, Leeds LS9 7TF, UK.
  • 4 UCL Genetics Institute, University College London, London WC1E 6BT, UK.
  • 5 Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds LS9 7TF, UK.
  • 6 UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
  • 7 Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
  • 8 Bradford School of Optometry and Visual Science, University of Bradford, Bradford BD7 1DP, UK.
  • 9 Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
  • 10 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.
  • 11 UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • 12 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.
  • 13 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.
PMID: 25983245 DOI: 10.1016/j.ajhg.2015.04.006
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.

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