FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)

Abstract 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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Marwa Zafarullah, Hiu-Tung Tang, Blythe Durbin-Johnson, Emily Fourie, David Hessl, Susan M. Rivera, Flora Tassone
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b90334eda9354033980967de34242011
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b90334eda9354033980967de34242011
record_format	dspace
spelling	oai:doaj.org-article:b90334eda9354033980967de342420112021-12-02T15:39:39ZFMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)10.1038/s41598-020-67946-y2045-2322https://doaj.org/article/b90334eda9354033980967de342420112020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-67946-yhttps://doaj.org/toc/2045-2322Abstract 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.Marwa ZafarullahHiu-Tung TangBlythe Durbin-JohnsonEmily FourieDavid HesslSusan M. RiveraFlora TassoneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marwa Zafarullah Hiu-Tung Tang Blythe Durbin-Johnson Emily Fourie David Hessl Susan M. Rivera Flora Tassone FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)
description	Abstract 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.
format	article
author	Marwa Zafarullah Hiu-Tung Tang Blythe Durbin-Johnson Emily Fourie David Hessl Susan M. Rivera Flora Tassone
author_facet	Marwa Zafarullah Hiu-Tung Tang Blythe Durbin-Johnson Emily Fourie David Hessl Susan M. Rivera Flora Tassone
author_sort	Marwa Zafarullah
title	FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)
title_short	FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)
title_full	FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)
title_fullStr	FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)
title_full_unstemmed	FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)
title_sort	fmr1 locus isoforms: potential biomarker candidates in fragile x-associated tremor/ataxia syndrome (fxtas)
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/b90334eda9354033980967de34242011
work_keys_str_mv	AT marwazafarullah fmr1locusisoformspotentialbiomarkercandidatesinfragilexassociatedtremorataxiasyndromefxtas AT hiutungtang fmr1locusisoformspotentialbiomarkercandidatesinfragilexassociatedtremorataxiasyndromefxtas AT blythedurbinjohnson fmr1locusisoformspotentialbiomarkercandidatesinfragilexassociatedtremorataxiasyndromefxtas AT emilyfourie fmr1locusisoformspotentialbiomarkercandidatesinfragilexassociatedtremorataxiasyndromefxtas AT davidhessl fmr1locusisoformspotentialbiomarkercandidatesinfragilexassociatedtremorataxiasyndromefxtas AT susanmrivera fmr1locusisoformspotentialbiomarkercandidatesinfragilexassociatedtremorataxiasyndromefxtas AT floratassone fmr1locusisoformspotentialbiomarkercandidatesinfragilexassociatedtremorataxiasyndromefxtas
_version_	1718385895670808576

FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)

Ejemplares similares