A novel TARDBP insertion/deletion mutation in the flail arm variant of amyotrophic lateral sclerosis

Jennifer A. Solski, Shu Yang, Garth A. Nicholson, Natasha Luquin, Kelly L. Williams, Ruvini Fernando, Roger Pamphlett, Ian P. Blair*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Phenotypic variation in amyotrophic lateral sclerosis (ALS) is common, and one atypical form is the flail arm variant (FAV). Some classic ALS patients carry TARDBP mutations, and so we sought to establish whether TARDBP mutations are also present in the FAV of ALS. Mutation analysis of TARDBP, the gene encoding TDP-43, was performed in cohorts of classic and FAV ALS patients. An analysis of mutation effects was performed in patient fibroblasts. Results showed that a novel heterozygous in-frame insertion/deletion (indel), c.1158-1159delAT; c.1158-1159insCACCAACC, was identified in a highly conserved region encoding the glycine-rich area of TDP-43 in a patient with FAV. This indel was confirmed in the proband's mother, an obligate carrier, and was absent from 480 ethnically-matched control individuals. Transcription of the mutant allele was confirmed. Under induced stress, indel-mutant fibroblasts showed a loss of normal nuclear TDP-43 immunoreactivity and formation of cytoplasmic inclusions of TDP-43, consistent with features seen in affected neurons. In conclusion, TARDBP missense mutations have previously been reported in classic ALS and frontotemporal lobar degeneration. The identification of a TARDBP indel mutation in a patient with FAV extends the spectrum of mutations and further supports the role of TDP-43 in a range of neurodegenerative phenotypes.

Original languageEnglish
Pages (from-to)465-470
Number of pages6
JournalAmyotrophic Lateral Sclerosis
Issue number5
Publication statusPublished - Sept 2012
Externally publishedYes


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