Tags

Type your tag names separated by a space and hit enter

Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17.
Mol Cell Biol 2000; 20(11):4036-48MC

Abstract

Frontotemporal dementia accounts for a significant fraction of dementia cases. Frontotemporal dementia with parkinsonism linked to chromosome 17 is associated with either exonic or intronic mutations in the tau gene. This highlights the involvement of aberrant pre-mRNA splicing in the pathogenesis of neurodegenerative disorders. Little is known about the molecular mechanisms of the splicing defects underlying these diseases. To establish a model system for studying the role of pre-mRNA splicing in neurodegenerative diseases, we have constructed a tau minigene that reproduces tau alternative splicing in both cultured cells and in vitro biochemical assays. We demonstrate that mutations in a nonconserved intronic region of the human tau gene lead to increased splicing between exon 10 and exon 11. Systematic biochemical analyses indicate the importance of U1 snRNP and, to a lesser extent, U6 snRNP in differentially recognizing wild-type versus intron mutant tau pre-mRNAs. Gel mobility shift assays with purified U1 snRNP and oligonucleotide-directed RNase H cleavage experiments support the idea that the intronic mutations destabilize a stem-loop structure that sequesters the 5' splice site downstream of exon 10 in tau pre-mRNA, leading to increases in U1 snRNP binding and in splicing between exon 10 and exon 11. Thus, mutations in nonconserved intronic regions that increase rather than decrease alternative splicing can be an important pathogenic mechanism for the development of human diseases.

Authors+Show Affiliations

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10805746

Citation

Jiang, Z, et al. "Aberrant Splicing of Tau pre-mRNA Caused By Intronic Mutations Associated With the Inherited Dementia Frontotemporal Dementia With Parkinsonism Linked to Chromosome 17." Molecular and Cellular Biology, vol. 20, no. 11, 2000, pp. 4036-48.
Jiang Z, Cote J, Kwon JM, et al. Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17. Mol Cell Biol. 2000;20(11):4036-48.
Jiang, Z., Cote, J., Kwon, J. M., Goate, A. M., & Wu, J. Y. (2000). Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17. Molecular and Cellular Biology, 20(11), pp. 4036-48.
Jiang Z, et al. Aberrant Splicing of Tau pre-mRNA Caused By Intronic Mutations Associated With the Inherited Dementia Frontotemporal Dementia With Parkinsonism Linked to Chromosome 17. Mol Cell Biol. 2000;20(11):4036-48. PubMed PMID: 10805746.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17. AU - Jiang,Z, AU - Cote,J, AU - Kwon,J M, AU - Goate,A M, AU - Wu,J Y, PY - 2000/5/11/pubmed PY - 2000/7/8/medline PY - 2000/5/11/entrez SP - 4036 EP - 48 JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 20 IS - 11 N2 - Frontotemporal dementia accounts for a significant fraction of dementia cases. Frontotemporal dementia with parkinsonism linked to chromosome 17 is associated with either exonic or intronic mutations in the tau gene. This highlights the involvement of aberrant pre-mRNA splicing in the pathogenesis of neurodegenerative disorders. Little is known about the molecular mechanisms of the splicing defects underlying these diseases. To establish a model system for studying the role of pre-mRNA splicing in neurodegenerative diseases, we have constructed a tau minigene that reproduces tau alternative splicing in both cultured cells and in vitro biochemical assays. We demonstrate that mutations in a nonconserved intronic region of the human tau gene lead to increased splicing between exon 10 and exon 11. Systematic biochemical analyses indicate the importance of U1 snRNP and, to a lesser extent, U6 snRNP in differentially recognizing wild-type versus intron mutant tau pre-mRNAs. Gel mobility shift assays with purified U1 snRNP and oligonucleotide-directed RNase H cleavage experiments support the idea that the intronic mutations destabilize a stem-loop structure that sequesters the 5' splice site downstream of exon 10 in tau pre-mRNA, leading to increases in U1 snRNP binding and in splicing between exon 10 and exon 11. Thus, mutations in nonconserved intronic regions that increase rather than decrease alternative splicing can be an important pathogenic mechanism for the development of human diseases. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/10805746/Aberrant_splicing_of_tau_pre_mRNA_caused_by_intronic_mutations_associated_with_the_inherited_dementia_frontotemporal_dementia_with_parkinsonism_linked_to_chromosome_17_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=10805746 DB - PRIME DP - Unbound Medicine ER -