Alternative Splicing of Exon 14 Determines Nuclear or Cytoplasmic Localisation of FMR1 Protein Isoforms
Abstract
Impaired expression of the FMR1 gene is responsible for the fragile X mental retardation syndrome. The FMR1 gene encodes a cytoplasmic protein with RNA-binding properties. Its complex alternative splicing leads to several isoforms, whose abundance and specific functions in the cell are not known. We have cloned in expression vectors, cDNAs corresponding to several isoforms. Western blot comparison of the pattern of endogenous FMR1 proteins with these transfected isoforms allowed the tentative identification of the major endogenous isoform as ISO 7 and of a minor band as an isoform lacking exon 14 sequences (ISO 6 or ISO 12), while some other isoforms (ISO 4, ISO 5) were not expressed at detectable levels. Surprisingly, in immunofluorescence studies, the transfected splice variants that exclude exon 14 sequences (and have alternate C-terminal regions) were shown to be nuclear. Such differential localisation was however not seen in subcellular fractionation studies. Analysis of various deletion mutants suggests the presence of a cytoplasmic retention domain encoded in exon 14 and of a nuclear association domain encoded within the first eight exons that appear however to lack a typical nuclear localisation signal.
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FMRP is an RNA-binding protein, and only its cytoplasmic function has been well characterized.
“FMRP is an RNA-binding protein, and, despite its clear shuttling from the nucleus to the cytoplasm (59,60), only the cytoplasmic function of FMRP has been well characterized.”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [60]
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- Authors
- Sittler, A., Devys, D., Weber, C., & Mandel, J.-L.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Mandel, J.-L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1996-01-01
- Volume
- 5
- Issue
- 1
- Pages
- 95-102
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2100505524
- Cited by
- 198
- References
- 35
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 7 · 2015: 3 · 2014: 5 · 2013: 14 · 2012: 7
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Centre National de la Recherche Scientifique
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- FMR1 gene, fragile X syndrome, alternative splicing, exon 14, protein isoforms, subcellular localization, C-terminal domain, RNA-binding proteins, isoform expression
- MeSH terms
- Amino Acid Sequence, Animals, Cell Fractionation, Cell Line, Cell Nucleus, Chlorocebus aethiops, Cytoplasm, Exons, HeLa Cells, Humans, Molecular Sequence Data, Molecular Weight, Nerve Tissue Proteins, Recombinant Fusion Proteins, RNA, Messenger, 3T3 Cells, RNA-Binding Proteins, Sequence Deletion, Alternative Splicing, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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