Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17

L. Varani, M. Hasegawa, M. G. Spillantini, M. J. Smith, J. R. Murrell, Bernardino Ghetti, A. Klug, M. Goedert, G. Varani

Research output: Contribution to journalArticle

181 Citations (Scopus)

Abstract

Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Intronic mutations and some missense mutations increase splicing in of exon 10, leading to an increased ratio of four-repeat to three-repeat tau isoforms. Secondary structure predictions have led to the proposal that intronic mutations and one missense mutation destabilize a putative RNA stem-loop structure located close to the splice-donor site of the intron after exon 10. We have determined the three-dimensional structure of this tau exon 10 splicing regulatory element RNA by NMR spectroscopy. We show that it forms a stable, folded stem-loop structure whose thermodynamic stability is reduced by frontotemporal dementia and parkinsonism linked to chromosome 17 mutations and increased by compensatory mutations. By exon trapping, the reduction in thermodynamic stability is correlated with increased splicing in of exon 10.

Original languageEnglish (US)
Pages (from-to)8229-8234
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number14
DOIs
StatePublished - Jul 6 1999
Externally publishedYes

Fingerprint

Frontotemporal Dementia
Chromosomes, Human, Pair 17
Parkinsonian Disorders
Exons
RNA
Mutation
Missense Mutation
Thermodynamics
RNA Splice Sites
Introns
Protein Isoforms
Magnetic Resonance Spectroscopy
Genes

Keywords

  • Alternative mRNA splicing
  • Intronic mutations
  • Stem-loop RNA structure

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17. / Varani, L.; Hasegawa, M.; Spillantini, M. G.; Smith, M. J.; Murrell, J. R.; Ghetti, Bernardino; Klug, A.; Goedert, M.; Varani, G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 14, 06.07.1999, p. 8229-8234.

Research output: Contribution to journalArticle

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AU - Hasegawa, M.

AU - Spillantini, M. G.

AU - Smith, M. J.

AU - Murrell, J. R.

AU - Ghetti, Bernardino

AU - Klug, A.

AU - Goedert, M.

AU - Varani, G.

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AB - Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Intronic mutations and some missense mutations increase splicing in of exon 10, leading to an increased ratio of four-repeat to three-repeat tau isoforms. Secondary structure predictions have led to the proposal that intronic mutations and one missense mutation destabilize a putative RNA stem-loop structure located close to the splice-donor site of the intron after exon 10. We have determined the three-dimensional structure of this tau exon 10 splicing regulatory element RNA by NMR spectroscopy. We show that it forms a stable, folded stem-loop structure whose thermodynamic stability is reduced by frontotemporal dementia and parkinsonism linked to chromosome 17 mutations and increased by compensatory mutations. By exon trapping, the reduction in thermodynamic stability is correlated with increased splicing in of exon 10.

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