Structure and Alternative Splicing of the Antisense FMR1 (ASFMR1) Gene.
ASFMR1
Alternative Splicing
FMR1
Fragile X-associated Tremor/ataxia Syndrome
Isoforms
Long Read Sequencing
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Apr 2023
Apr 2023
Historique:
received:
18
04
2022
accepted:
10
12
2022
pubmed:
5
1
2023
medline:
8
3
2023
entrez:
4
1
2023
Statut:
ppublish
Résumé
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by an expansion of 55-200 CGG repeats (premutation) in the 5'-UTR of the FMR1 gene. Bidirectional transcription at FMR1 locus has been demonstrated and specific alternative splicing of the Antisense FMR1 (ASFMR1) gene has been proposed to have a contributing role in the pathogenesis of FXTAS. The structure of ASFMR1 gene is still uncharacterized and it is currently unknown how many isoforms of the gene are expressed and at what level in premutation carriers (PM) and if they may contribute to the premutation pathology. In this study, we characterized the ASFMR1 gene structure and the transcriptional landscape by using PacBio SMRT sequencing with target enrichment (IDT customized probe panel). We identified 45 ASFMR1 isoforms ranging in sizes from 523 bp to 6 Kb, spanning approximately 59 kb of genomic DNA. Multiplexing and sequencing of six human brain samples from PM samples and normal control (HC) were carried out on the PacBio Sequel platform. We validated the presence of these isoforms by qRT-PCR and Sanger sequencing and characterized the acceptor and donor splicing site consensus sequences. Consistent with previous studies conducted in other tissue types, we found a high expression of ASFMR1 isoform Iso131bp in brain samples of PM as compared to HC, while no differences in expression levels were observed for the newly identified isoforms IsoAS1 and IsoAS2. We investigated the role of the splicing regulatory protein Sam68 which we did not observe in the alternative splicing of the ASFMR1 gene. Our study provides a useful insight into the structure of ASFMR1 gene and transcriptional landscape along with the expression pattern of various newly identified novel isoforms and on their potential role in premutation pathology.
Identifiants
pubmed: 36598648
doi: 10.1007/s12035-022-03176-9
pii: 10.1007/s12035-022-03176-9
pmc: PMC10461537
mid: NIHMS1918757
doi:
Substances chimiques
Protein Isoforms
0
Fragile X Mental Retardation Protein
139135-51-6
FMR1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2051-2061Subventions
Organisme : NICHD NIH HHS
ID : R01 HD036071
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH078041
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS110100
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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