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, Colin A. Johnson, Ian M. Carr, Bart P. Leroy, Elfride De Baere, Chris F. Inglehearn, Andrew R. Webster, Carmel Toomes, Manir Ali

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)948-54
Number of pages7
JournalAmerican Journal of Human Genetics
Volume96
Issue number6
Early online date14 May 2015
DOIs
Publication statusPublished - 4 Jun 2015

Keywords

  • Adult
  • Base Sequence
  • Exome/genetics
  • Homozygote
  • Humans
  • Immunohistochemistry
  • Macular Degeneration/genetics
  • Membrane Proteins/genetics
  • Molecular Sequence Data
  • Mutation/genetics
  • Pakistan/ethnology
  • Pedigree
  • Retinal Dystrophies/genetics
  • Sequence Analysis, DNA
  • United Kingdom

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