Mutation in the tau gene in familial multiple system tauopathy with presenile dementia - PubMed (original) (raw)

Mutation in the tau gene in familial multiple system tauopathy with presenile dementia

M G Spillantini et al. Proc Natl Acad Sci U S A. 1998.

Abstract

Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology. It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown. We now report a G to A transition in the intron following exon 10 of the gene for microtubule-associated protein tau in familial MSTD. The mutation is located at the 3' neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer's disease and other tauopathies.

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Figures

Figure 1

Figure 1

Pedigree of the family with MSTD. Blackened symbols denote affected individuals. Black dots indicate individuals from whom DNA was available and tested by sequencing for the presence of the G to A mutation in the nucleotide adjacent to the exon 10 splice-donor site of the tau gene. The triangle identifies twins (it is not known whether they were mono- or dizygotic). Generation numbers are shown to the left.

Figure 2

Figure 2

Double-stranded DNA sequence of the exon 10-intron junction of the tau gene from an unaffected (labeled N) and an affected (labeled A) member of the family with MSTD. The position of the heterozygous G to A mutation is marked by the arrow.

Figure 3

Figure 3

Nucleotide sequence of the exon 10–intron junctions of the tau gene (a) and structure of the predicted stem-loop in the pre-mRNA (b). The exon sequences are shown in capital and the intron sequences in small letters. Amino acid numbering corresponds to the 441-amino acid isoform of human brain tau. The G to A transition responsible for familial MSTD is shown.

Figure 4

Figure 4

(a) Schematic representation of the six human brain tau isoforms, with the alternatively spliced exons shown in red (exon 2), green (exon 3), and yellow (exon 10). The microtubule-binding repeats are indicated by black bars. (b) Immunoblots of dephosphorylated soluble tau protein from the frontal cortex of a control subject (lane 2) and a patient with familial MSTD (lane 3) using anti-tau serum BR133. Similar results were obtained with anti-tau serum BR134. Six tau isoforms are present in lanes 2 and 3. They align with the six recombinant human brain tau isoforms (lane 1). In the frontal cortex from the familial MSTD patient, tau isoforms with four repeats (isoforms D, E, and F) are more abundant and tau isoforms with three repeats (isoforms A, B, and C) are less abundant than in frontal cortex from the control. Arrows indicate the positions of tau isoforms with four repeats.

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