A Novel Mutation at Position +12 in the Intron following Exon 10 of the Tau Gene in Familial Frontotemporal Dementia (FTD-Kumamoto) Minoru Yasuda, MD,* Junichi Takamatsu, MD,† Ian D’Souza, PhD,‡§ R. Anthony Crowther, PhD,  Toshio Kawamata, MD,* Masato Hasegawa, PhD,¶ Hiroshi Hasegawa, MD,* Maria Grazia Spillantini, PhD,# Satoshi Tanimukai, MD,* Parvoneh Poorkaj, PhD,‡§ Luca Varani,  Gabriele Varani, PhD,  Takeshi Iwatsubo, MD,¶ Michel Goedert, MD, PhD,  Gerard D. Schellenberg, PhD,‡§** and Chikako Tanaka, MD* Exonic and intronic mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe a new mutation, consisting of a C-to-T transition at position 12 of the intron following exon 10 of the tau gene in the Kumamoto pedigree, showing frontotemporal dementia. The mutation caused a marked reduction in melting temperature of the tau exon 10 –splicing regulatory element RNA and a large increase in exon 10 –containing transcripts. Brain tissue from affected individuals showed an abnormal preponderance of exon 10 –containing transcripts that was reflected at the protein level by an overproduction of tau isoforms with four microtubule-binding repeats. Immunostaining revealed the presence of tau aggregates in degenerating neurons and glial cells. Isolated tau filaments had a twisted ribbon-like morphology and were made of hyperphosphorylated four-repeat tau isoforms. The additional mutation located close to the splice-donor site of the intron following exon 10 of the tau gene supports the view that intronic mutations exercize their pathogenic effect by destabilizing RNA secondary structure. Yasuda M, Takamatsu J, D’Souza I, Crowther RA, Kawamata T, Hasegawa M, Hasegawa H, Spillantini MG, Tanimukai S, Poorkaj P, Varani L, Varani G, Iwatsubo T, Goedert M, Schellenberg GD, Tanaka C. A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto). Ann Neurol 2000;47:422– 429 Abundant neurofibrillary lesions made of microtubule- associated protein tau constitute a defining neuro- pathological characteristic of Alzheimer’s disease. 1 Fila- mentous tau protein deposits are also the defining neuropathological characteristic of other neurodegen- erative diseases, many of which are frontotemporal de- mentias or movement disorders that have been sub- sumed under the heading of “Pick complex.” 2 Recent work has shown that mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). 3–21 Known tau mutations are either intronic mutations located close to the splice-donor site of the intron following exon 10 or missense, deletion, or silent mutations in the coding region. Six tau isoforms are produced in adult human brain by alternative mRNA splicing from a single gene. 22 They differ from each other by the presence or absence of 29- or 58-amino acid inserts located in the amino- terminal half and an additional 31-amino acid repeat located in the carboxy-terminal half. Inclusion of the latter, which is encoded by exon 10, produces the three isoforms with four repeats each 23 ; the other three iso- forms have three repeats each. The repeats and some adjoining sequences constitute the microtubule-binding domains of tau. 24,25 Similar levels of three-repeat and four-repeat tau isoforms are found in normal cerebral cortex, 26 and the tau filaments from Alzheimer’s dis- ease brain contain all six tau isoforms in a hyperphos- phorylated state. 27 From the *Hyogo Institute for Aging Brain and Cognitive Disor- ders, Himeji, †Division of Clinical Research, Kikuchi National Hos- pital, Kumamoto, and ¶Department of Neuropathology and Neu- roscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; ‡Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, and §Division of Gerontology and Geriatric Medicine, Department of Medicine, and **Departments of Pharmacology and Neurology, University of Washington, Seattle, WA; and  Medical Research Council Laboratory of Molecular Biology and #Department of Neu- rology, Adrian Building, University of Cambridge, Cambridge, UK. Received Oct 14, 1999, and in revised form Nov 29. Accepted for publication Nov 30, 1999. Address correspondence to Dr Yasuda, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan. ORIGINAL ARTICLES 422 Copyright © 2000 by the American Neurological Association