Neurogenetics (2005) 6: 91–95 DOI 10.1007/s10048-005-0210-y LETTER TO THE EDITORS Manuela Neumann . Silvia Diekmann . Uwe Bertsch . Ben Vanmassenhove . Bernhard Bogerts . Hans A. Kretzschmar Novel G335V mutation in the tau gene associated with early onset familial frontotemporal dementia Received: 14 October 2004 / Accepted: 27 December 2004 / Published online: 12 March 2005 # Springer-Verlag 2005 Abstract Mutations in the tau gene cause familial fronto- temporal dementia and parkinsonism linked to chromo- some 17. Here we describe a novel missense mutation in exon 12 of the tau gene, G335V, in a German family with frontotemporal dementia of early age at onset, in the third decade of life. Functional analysis of recombinant tau pro- tein with the G335V mutation showed a dramatically re- duced ability to promote microtubule assembly and a more rapid and accelerated tau filament formation, suggesting that the primary effect of the mutation might be the pro- vision of a pool of unbound tau making it available for aberrant tau aggregation. Keywords FTDP-17 . Tauopathy . Frontotemporal dementia . Tau Introduction The identification of mutations in the tau gene in familial frontotemporal dementia and parkinsonism linked to chro- mosome 17 (FTDP-17) has established the important role of the tau protein as a cause of neurodegeneration [1–3]. The neuropathological hallmarks of FTDP-17 with tau gene mutations are prominent filamentous deposits con- sisting of the microtubule-associated protein tau in neuronal and glial cells. So far, 34 different pathogenic tau gene mutations have been described. These include missense, deletion or silent mutations in the coding region, or intronic mutations located close to the splice-donor site of the in- tron following exon 10 [4]. Functionally, the mutations fall into two categories. All intronic and some exon 10 muta- tions influence the alternative splicing of tau pre-mRNA, thereby disturbing the normal splicing balance of exon 10 [2, 3, 5]. By contrast, most missense mutations reduce the ability of tau to interact with microtubules (MTs) [6–8], except for the S305N and the recently identified Q336R mutation, which lead to an increased ability of tau to promote MT assembly [9, 10]. Moreover, several missense mutations also stimulate the in vitro assembly of tau into filaments [8, 11–13]. Here we report a novel missense mutation (G335V) in the tau gene in a German family with early onset frontotemporal dementia. In contrast to the effect of the adjacent Q336R mutation [10], the G335V mutation results in a dramatically reduced ability of tau to promote MT assembly. In addition, the G335V mutation leads to an increased heparin-induced assembly of recombinant tau into filaments. Materials and methods Genetic analysis Genomic DNA was extracted from whole blood using the Wizard Genomic DNA Purification Kit (Promega, Mann- heim, Germany). All exons of the tau gene were amplified by polymerase chain reaction (PCR) using primers from the intronic sequences surrounding the exons [1]. The PCR products were checked for size by agarose gel electropho- resis and purified using QIAquick spin columns (Qiagen). DNA sequencing was carried out using the SequiTherm EXCEL long-read kit LC (Epicenture Technologies, Mad- ison, Wis.) and 5′ 41-IRD labelled oligonucleotides. The labelled products were separated by denaturing gel electro- phoresis on a 4.3% Long-Ranger gel (AT Biochem, Mal- vern, Wis.) and monitored using an automated DNA sequencing system (Model 4000L, LI-COR, Lincoln, N. M. Neumann and S. Diekmann contributed equally to this work. M. Neumann . U. Bertsch . B. Vanmassenhove . H. A. Kretzschmar (*) Center for Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany e-mail: Hans.Kretzschmar@med.uni-muenchen.de Tel.: +49-89-218078000 Fax: +49-89-218078037 S. Diekmann . B. Bogerts Department of Psychiatry, University of Magdeburg, Magdeburg, Germany