Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia

Anna Lotta Kaivorinne, Virpi Moilanen, Marko Kervinen, Alan E. Renton, Bryan J. Traynor, Kari Majamaa, Anne M. Remes

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Frontotemporal lobar degeneration (FTLD) is a genetically heterogenous syndrome and has been associated most recently with a hexanucleotide repeat expansion within the C9ORF72 gene. Pathogenic TDP-43 gene (TARDBP) mutations have been identified in amyotrophic lateral sclerosis, but the role of TARDBP mutations in FTLD is more contradictory. To investigate the role of TARDBP mutations in a clinical series of Finnish FTLD patients, we sequenced TARDBP exons 1 to 6 in 77 FTLD patients. No evident pathogenic mutations were found. We identified a novel heterozygous c.876-878delCAG sequence variant in 2 related patients with behavioral variant frontotemporal dementia without amyotrophic lateral sclerosis. The variant is predicted to cause an amino acid deletion of serine at position 292 (p.Ser292del). However, p.Ser292del was also found in 1 healthy middle-aged control. Interestingly, both patients carried the C9ORF72 expansion. Therefore, the TARDBP variant p.Ser292del might be considered a rare polymorphism and the C9ORF72 repeat expansion the actual disease-causing mutation in the family. Our results suggest that TARDBP mutations are a rare cause of FTLD. However, the interaction of several genetic factors needs to be taken into account when investigating neurodegenerative diseases.

Original languageEnglish
Pages (from-to)190-193
Number of pages4
JournalAlzheimer Disease and Associated Disorders
Volume28
Issue number2
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • C9ORF72
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Mutation
  • TARDBP
  • TDP-43

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