These authors equally contributed to this work.
Mutation in Brief
Mutation within TARDBP leads to Frontotemporal Dementia without motor neuron disease†
Article first published online: 4 AUG 2009
© 2009 Wiley-Liss, Inc.
Volume 30, Issue 11, pages E974–E983, November 2009
How to Cite
Borroni, B., Bonvicini, C., Alberici, A., Buratti, E., Agosti, C., Archetti, S., Papetti, A., Stuani, C., Di Luca, M., Gennarelli, M. and Padovani, A. (2009), Mutation within TARDBP leads to Frontotemporal Dementia without motor neuron disease. Hum. Mutat., 30: E974–E983. doi: 10.1002/humu.21100
Communicated by Michel Goossens
- Issue published online: 27 OCT 2009
- Article first published online: 4 AUG 2009
- Manuscript Accepted: 14 JUL 2009
- Manuscript Received: 16 MAY 2009
- The work was made possible by grant of “Centro per i disturbi del comportamento e per le malattie neurodegenerative, EULO” to AP. EB and CS are supported by Telethon and Eurasnet
- Cited By
- behavioral variant Frontotemporal Dementia;
- Frontotemporal Lobar Degeneration
It has been recently demonstrated that the 43-kDa transactive response (TAR)-DNA-binding protein (TARDBP) is the neuropathological hallmark of Frontotemporal Dementia (FTD) with ubiquitin-positive and tau-negative inclusions. Large series of FTD patients without motor neuron disease have been previously analysed, but no TARDBP mutation was identified. The aim of the present study was to evaluate whether TARDBP gene mutations may be associated with FTD. We report that a pathogenetic TARDBP mutation is causative of behavioural variant FTD (bvFTD). An aged woman in her seventies initially started to present apathy and depression associated with impairment in executive functions. The diagnosis of bvFTD (apathetic syndrome) was accomplished by three-year follow-up, and structural and functional neuroimaging. By five-years after onset, extensive electrophysiological investigations excluded subclinical motor neuron disease. In this patient, a single base substitution c.800A>G of TARDBP gene was identified. This mutation, already described as causative of ALS, predicted the amino acidic change arginine to serine at position 267 (N267S). In silico analysis demonstrated that this substitution generates a new phosphorylation site, and western blot analysis on lymphoblastoid cells reported a decrease of protein expression in N267S mutation carrier. Our study suggests that TARDBP mutations can be pathogenetic of bvFTD without motor neuron disease. TARDBP screening needs to be considered in FTD cases. © 2009 Wiley-Liss, Inc.