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Novel Tau Polymorphisms, Tau Haplotypes, and Splicing in Familial and Sporadic Frontotemporal Dementia
Maria-Jesús Sobrido, MD, PhD;
Bruce L. Miller, MD;
Necat Havlioglu, MD;
Victoria Zhukareva, PhD;
Zhihong Jiang, PhD;
Ziad S. Nasreddine, MD;
Virginia M.-Y. Lee, PhD;
Tiffany W. Chow, MD;
Kirk C. Wilhelmsen, MD, PhD;
Jeffrey L. Cummings, MD;
Jane Y. Wu, PhD;
Daniel H. Geschwind, MD, PhD
Arch Neurol. 2003;60:698-702.
Background A subset of familial cases (FTDP-17) of frontotemporal dementia (FTD) are caused by mutations in the tau gene. The role of tau gene mutations and haplotypes in sporadic FTD and the functional consequences of tau polymorphisms are unknown.
Objectives To investigate (1) the frequency of known FTDP-17 mutations in familial and sporadic FTD and compare these results with previous studies; (2) whether the tau H1 haplotype is associated with FTD; and (3) the functional effect of intronic tau sequence variations.
Patients and Methods Patients with familial and sporadic FTD were screened for mutations in the microtubule-binding region of tau. The frequencies of tau haplotypes and genotypes were compared between patients with FTD and control subjects. We analyzed the splicing effect of novel intronic polymorphisms associated with FTD.
Results The P301L mutation was detected in 11% of familial FTD cases. The H1 haplotype was not overrepresented in patients with FTD, but the P301L mutation appeared on the background of the H2 tau haplotype. We identified 4 novel single nucleotide polymorphisms in intron 9 and a 9–base pair deletion in intron 4A. A C-to-T transition 177 base pairs upstream from exon 10 was significantly increased in patients with FTD compared with controls. Direct analysis of brain tissue from a patient with this variant showed an increase in exon 10–containing tau transcripts.
Conclusions Sequence variations in intronic or regulatory regions of tau may have previously unrecognized consequences leading to tau dysfunction and neurodegeneration.
From the Department of Neurology, The David Geffen School of Medicine at UCLA (University of California, Los Angeles), Los Angeles (Drs Sobrido, Cummings, and Geschwind); Department of Neurology, University of California, San Francisco (UCSF) School of Medicine (Dr Miller), and the Gallo Clinic and Research Center (Dr Wilhelmsen), San Francisco; Department of Pediatrics and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, Mo (Drs Havlioglu, Jiang, and Wu); Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia (Drs Zhukareva and Lee); Service de Neurologie, Hôpital Charles LeMoyne, Greenfield Park, Université de Sherbrooke, Sherbrooke, Québec (Dr Nasreddine); and Department of Neurology, University of Southern California/Rancho Los Amigos Medical Center, Downey (Dr Chow).
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