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Genetic and epigenetic study of ALS-discordant identical twins with double mutations in SOD1 and ARHGEF28
  1. Ming Zhang1,
  2. Zhengrui Xi1,
  3. Mahdi Ghani1,
  4. Peixin Jia2,
  5. Mrinal Pal2,
  6. Karolina Werynska1,
  7. Danielle Moreno1,
  8. Christine Sato1,
  9. Yan Liang1,
  10. Janice Robertson1,
  11. Arturas Petronis2,
  12. Lorne Zinman3,4,
  13. Ekaterina Rogaeva1,4
  1. 1 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
  2. 2 Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  3. 3 Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  4. 4 Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Professor Ekaterina Rogaeva, Tanz Centre for Neurodegenerative Diseases, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8; ekaterina.rogaeva{at}utoronto.ca

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Introduction

Amyotrophic lateral sclerosis (ALS) is characterised by a loss of motor neurons, leading to paralysis. Several autosomal dominant genes were implicated in ALS pathogenesis, such as SOD1, with over 180 reported mutations (http://alsod.iop.kcl.ac.uk/), including a p.T137A substitution.1 ,2 Recently, ARHGEF28, encoding an RNA binding protein involved in the aggregation of light neurofilaments in ALS, was suggested as a novel ALS gene (a heterozygous K280M>fs40X mutation was detected in three patients).3 ,4

Risk of ALS may be modulated by environmental factors, sex and ageing, which could be linked to epigenetic events (eg, DNA methylation). Monozygotic (MZ) twins provide the best opportunity to investigate environmental/epigenetic factors in disease development.5 Hence, we studied ALS-discordant MZ twins, including the evaluation of DNA methylation (DNAm) age, which is an accurate predictor of chronological age across different tissues.6 It is possible that DNAm age better reflects biological age than chronological age does, since age acceleration (DNAm age minus chronological age) was associated with several disorders and mortality.

Methods

Participants were recruited from the ALS Clinic at the Sunnybrook Health Sciences Centre. Genetic and epigenetic analyses were conducted as described in the online supplementary methods, including mutation analysis of SOD1 and C9orf72, NeuroX array, reverse transcription PCR (RT-PCR), whole genome DNA methylation array (HumanMethylation450 BeadChip) and bisulfite pyrosequencing.

Supplemental material

[jnnp-2016-313592supp.pdf]

Results

The MZ twins from a Canadian PED24 family of Italian origin were 52 years old at last examination and ALS-discordant for 17 years, with the second-born twin (9377) diagnosed with ALS at 35 years (figure 1 …

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Footnotes

  • Contributors MZ and ZX were responsible for the genetic and methylation studies including data analyses. MG was responsible for analysis of the NeuroX array. AP, PJ and MP helped with designing and conducting the pyrosequencing experiment. KW helped on bisulfite PCR. DM, CS and YL were involved in sample preparation and sequencing of ALS genes. JR assisted in sample collection. LZ was responsible for obtaining clinical findings. ER conceived and supervised the project, and drafted the manuscript, with MZ, ZX and LZ. All the authors critically reviewed and approved the final manuscript.

  • Funding This work was supported by the Canadian Consortium on Neurodegeneration in Aging (ER, MZ), Weston Brain Institute (ER, ZX, LZ), the James Hunter ALS Initiative and the Temerty Family Foundation (LZ, JR).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Ethics approval for this project was obtained by the ethics board of the Sunnybrook Health Sciences Centre.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • MZ and ZX contributed equally.

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