FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS).
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 07 2020
06 07 2020
Historique:
received:
29
12
2019
accepted:
18
05
2020
entrez:
8
7
2020
pubmed:
8
7
2020
medline:
15
12
2020
Statut:
epublish
Résumé
Fragile X associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele of 55-200 CGG repeats in the Fragile X mental retardation (FMR1) gene. It is currently unknown if and when an individual carrier of a premutation allele will develop FXTAS, as clinical assessment fails to identify carriers at risk before significant neurological symptoms are evident. The primary objective of this study was to investigate the alternative splicing landscape at the FMR1 locus in conjunction with brain measures in male individuals with a premutation allele enrolled in a very first longitudinal study, compared to age-matched healthy male controls, with the purpose of identifying biomarkers for early diagnosis, disease prediction and, a progression of FXTAS. Our findings indicate that increased expression of FMR1 mRNA isoforms, including Iso4/4b, Iso10/10b, as well as of the ASFMR1 mRNAs Iso131bp, are present in premutation carriers as compared to non-carrier healthy controls. More specifically, we observed a higher expression of Iso4/4b and Iso10/10b, which encode for truncated proteins, only in those premutation carriers who developed symptoms of FXTAS over time as compared to non-carrier healthy controls, suggesting a potential role in the development of the disorder. In addition, we found a significant association of these molecular changes with various measurements of brain morphology, including the middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), pons, and midbrain, indicating their potential contribution to the pathogenesis of FXTAS. Interestingly, the high expression levels of Iso4/4b observed both at visit 1 and visit 2 and found to be associated with a decrease in mean MCP width only in those individuals who developed FXTAS over time, suggests their role as potential biomarkers for early diagnosis of FXTAS.
Identifiants
pubmed: 32632326
doi: 10.1038/s41598-020-67946-y
pii: 10.1038/s41598-020-67946-y
pmc: PMC7338407
doi:
Substances chimiques
Biomarkers
0
FMR1 protein, human
0
Protein Isoforms
0
Fragile X Mental Retardation Protein
139135-51-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
11099Subventions
Organisme : NINDS NIH HHS
ID : R01 NS110100
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001860
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH078041
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD079125
Pays : United States
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