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

Abstract

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.

Key words::

• Amyotrophic lateral sclerosis
• flail arm
• TDP-43
• TARDBP
• mutation

Acknowledgements

We are grateful for the participation and contribution of patients and family members. We thank Carolyn Cecere for assistance with family and patient recruitment. This work was supported by the National Health and Medical Research Council of Australia, as well as a Bill Gole fellowship (to SY), a Peter Stearne grant from the MND Research Institute of Australia, and the Aimee Stacey and Ignatius Burnett MND Bequests.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.