Premium
Mutation within TARDBP leads to Frontotemporal Dementia without motor neuron disease
Author(s) -
Borroni B.,
Bonvicini C.,
Alberici A.,
Buratti E.,
Agosti C.,
Archetti S.,
Papetti A.,
Stuani C.,
Di Luca M.,
Gennarelli M.,
Padovani A.
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21100
Subject(s) - tardbp , frontotemporal dementia , amyotrophic lateral sclerosis , biology , mutation , dementia , genetics , c9orf72 , motor neuron , disease , neuroscience , medicine , gene , pathology , spinal cord
Abstract 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.