A genomic sequence analysis of the mouse and human
microtubule-associated protein tau
Maynard V. Olson,
Gerard D. Schellenberg
Geriatric Research Education Clinical Center 182-B, Veterans Affairs Puget Sound Health Care System, Seattle Division, 1660 S. Columbian Way,
Seattle, Washington 98108, USA
Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, Washington 98195, USA
Department of Medicine, University of Washington, Seattle, Washington 98195, USA
Department of Genetics, University of Washington, Seattle, Washington 98195, USA
Departments of Neurology and Pharmacology, University of Washington, Seattle, Washington 98195, USA
Received: 1 April 2001 / Accepted: 20 April 2001
Abstract. Microtubule associated protein tau (MAPT) encodes
the microtubule associated protein tau, the primary component of
neurofibrillary tangles found in Alzheimer’s disease and other neu-
rodegenerative disorders. Mutations in the coding and intronic
sequences of MAPT cause autosomal dominant frontotemporal
dementia (FTDP-17). MAPT is also a candidate gene for progres-
sive supranuclear palsy and hereditary dysphagic dementia. A hu-
man PAC (201 kb) and a mouse BAC (161 kb) containing the
entire MAPT and Mtapt genes, respectively, were identified and
sequenced. Comparative DNA sequence analysis revealed over
100 conserved non-repeat potential cis-acting regulatory se-
quences in or close to MAPT. Those islands with greater than 67%
nucleotide identity range in size from 20 to greater than 1700
nucleotides. Over 90 single nucleotide polymorphisms were iden-
tified in MAPT that are candidate susceptibility alleles for neuro-
degenerative disease. The 5Ј and 3Ј flanking genes for MAPT are
the corticotrophin-releasing factor receptor (CRFR) gene and
KIAA1267, a gene of unknown function expressed in brain.
Tau is a member of the microtubule-associated protein (MAP)
family found primarily in neurons, and at lower levels in oligo-
dendrocytes, astrocytes, and in some non-nervous system tissues
(LoPresti et al. 1995; Gu et al. 1996; Vanier et al. 1998). In vitro,
tau binds to microtubules and stimulates microtubule assembly. In
vivo, tau promotes microtubule assembly and stability and may
participate in axonal extension and maintenance (Caceres and
Kosik 1990; Caceres et al. 1991).
Expression of the gene encoding tau (MAPT in human, Mtapt
in mouse) is highly regulated, particularly at the RNA splicing
stage, and this regulation differs between rodents and humans.
MAPT has 15 exons, where 6 of 14 coding exons undergo alter-
native splicing (Fig. 1) (Himmler et al., 1989; Himmler, 1989;
Andreadis et al., 1992). In the fetal central nervous system (CNS),
a single tau isoform is produced lacking all alternatively spliced
exons. In the adult human CNS, six splice variants are produced by
inclusion of alternative exons 2, 3, and 10 (Goedert et al. 1989)
(Fig. 1). In contrast, in the adult rodent brain, only three isoforms
are present, with all forms containing exon 10 (E10; Kosik et al.
1989) and E2 and E3 being alternatively spliced (Collet et al.
1997). Tau has microtubule-binding domains that are imperfect 18
amino acid repeats separated by 13–14 amino acid inter-repeat
regions that are dissimilar; E10 encodes one binding repeat and
one inter-repeat. Depending on whether E10 is excluded or in-
cluded, tau has either three (3R tau) or four (4R tau) microtubule-
binding repeats, respectively. The functional consequence of add-
ing E10 is that 4R tau binds microtubules with a higher affinity
compared with 3R tau(Butner and Kirschner 1991; Gustke et al.
1994). In adult human brain, the 3R/4R ratio is approximately 1
(Hong et al., 1998), while in rodent brain only 4R tau is made
(Kosik et al. 1989). The use of other alternatively spliced exons
(4a, 6, and 8) appears to be confined to the peripheral nervous
system in humans, though low levels of E4a- and E6-containing
transcripts are found in human and rodent brain (Georgieff et al.
1991, 1993; Mavilia et al. 1993, 1994; Boyne et al. 1995; Wei and
Andreadis 1998). In addition, in some mouse transcripts, the intron
between E13 and E14 is removed by RNA splicing (Lee et al.
1988), while in other mouse transcripts and in all rat and human
transcripts described to date, the equivalent sequences are retained.
Poly-adenylation site usage is also regulated, and MAPT tran-
scripts have either a short 200- to 250-nt 3Ј untranslated region
(3ЈUTR) or a much longer ∼4kb 3ЈUTR (Goedert et al. 1988; Sadot
et al. 1994).
Mutations in MAPT cause frontotemporal dementia, Chromo-
some (Chr) 17 type (FTDP-17) (Clark et al. 1998; Hutton et al.
1998; Spillantini et al. 1998; Poorkaj et al. 1998), an autosomal
dominant neurodegenerative disease. Different MAPT mutations
cause FTDP-17 by different mechanisms. Some mutations alter the
biochemical properties of tau, resulting in decreased microtubule-
binding capacity or decreased rates of tau-stimulated microtubule
polymerization (e.g., P301L, V337M; Hong et al. 1998). Other
mutations disrupt the normal regulation of E10 splicing, either
increasing or decreasing the inclusion of E10 (Hutton et al. 1998;
D’Souza et al. 1999; D’Souza and Schellenberg 2000). For some
FTDP-17 families, genetic linkage analysis has clearly localized
the disease-causing defect to the MAPT region of Chr 17 and yet
no mutations have been identified in the MAPT open reading
frame or in the intronic sequences immediately flanking exons
[e.g., the HDDD2 kindred (Lendon et al. 1998)]. Mutations in
these families are presumably in regulatory sequences within in-
trons or in regulatory sequences flanking the gene.
MAPT is a candidate gene for a number of other neurodegen-
erative disorders including corticobasal degeneration (CBD), pro-
gressive supranuclear palsy (PSP), Picks disease, and amyotrophy
lateral sclerosis parkinsonism dementia complex of Guam. A ge-
To whom correspondence should be addressed at GRECC 182-B, Vet-
erans Affairs Puget Sound Health Care System, 1660 S. Columbian Way,
Seattle, WA 98108. Telephone: (206) 764-2701. FAX: (206) 764-2569.
Correspondence to: G.D. Schellenberg; email: Zachdad@U.Washington.
Mammalian Genome 12, 700–712 (2001).
© Springer-Verlag New York Inc. 2001