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A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression

We describe the characterisation of a variable number tandem repeat (VNTR) domain within intron 1 of the amyotrophic lateral sclerosis (ALS) risk gene CFAP410 (Cilia and flagella associated protein 410) (previously known as C21orf2), providing insight into how this domain could support differential...

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Autores principales: Marshall, Jack N. G., Fröhlich, Alexander, Li, Li, Pfaff, Abigail L., Middlehurst, Ben, Spargo, Thomas P., Iacoangeli, Alfredo, Lang, Bing, Al-Chalabi, Ammar, Koks, Sulev, Bubb, Vivien J., Quinn, John P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484465/
https://www.ncbi.nlm.nih.gov/pubmed/36131690
http://dx.doi.org/10.3389/fnmol.2022.954928
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author Marshall, Jack N. G.
Fröhlich, Alexander
Li, Li
Pfaff, Abigail L.
Middlehurst, Ben
Spargo, Thomas P.
Iacoangeli, Alfredo
Lang, Bing
Al-Chalabi, Ammar
Koks, Sulev
Bubb, Vivien J.
Quinn, John P.
author_facet Marshall, Jack N. G.
Fröhlich, Alexander
Li, Li
Pfaff, Abigail L.
Middlehurst, Ben
Spargo, Thomas P.
Iacoangeli, Alfredo
Lang, Bing
Al-Chalabi, Ammar
Koks, Sulev
Bubb, Vivien J.
Quinn, John P.
author_sort Marshall, Jack N. G.
collection PubMed
description We describe the characterisation of a variable number tandem repeat (VNTR) domain within intron 1 of the amyotrophic lateral sclerosis (ALS) risk gene CFAP410 (Cilia and flagella associated protein 410) (previously known as C21orf2), providing insight into how this domain could support differential gene expression and thus be a modulator of ALS progression or risk. We demonstrated the VNTR was functional in a reporter gene assay in the HEK293 cell line, exhibiting both the properties of an activator domain and a transcriptional start site, and that the differential expression was directed by distinct repeat number in the VNTR. These properties embedded in the VNTR demonstrated the potential for this VNTR to modulate CFAP410 expression. We extrapolated these findings in silico by utilisation of tagging SNPs for the two most common VNTR alleles to establish a correlation with endogenous gene expression. Consistent with in vitro data, CFAP410 isoform expression was found to be variable in the brain. Furthermore, although the number of matched controls was low, there was evidence for one specific isoform being correlated with lower expression in those with ALS. To address if the genotype of the VNTR was associated with ALS risk, we characterised the variation of the CFAP410 VNTR in ALS cases and matched controls by PCR analysis of the VNTR length, defining eight alleles of the VNTR. No significant difference was observed between cases and controls, we noted, however, the cohort was unlikely to contain sufficient power to enable any firm conclusion to be drawn from this analysis. This data demonstrated that the VNTR domain has the potential to modulate CFAP410 expression as a regulatory element that could play a role in its tissue-specific and stimulus-inducible regulation that could impact the mechanism by which CFAP410 is involved in ALS.
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spelling pubmed-94844652022-09-20 A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression Marshall, Jack N. G. Fröhlich, Alexander Li, Li Pfaff, Abigail L. Middlehurst, Ben Spargo, Thomas P. Iacoangeli, Alfredo Lang, Bing Al-Chalabi, Ammar Koks, Sulev Bubb, Vivien J. Quinn, John P. Front Mol Neurosci Molecular Neuroscience We describe the characterisation of a variable number tandem repeat (VNTR) domain within intron 1 of the amyotrophic lateral sclerosis (ALS) risk gene CFAP410 (Cilia and flagella associated protein 410) (previously known as C21orf2), providing insight into how this domain could support differential gene expression and thus be a modulator of ALS progression or risk. We demonstrated the VNTR was functional in a reporter gene assay in the HEK293 cell line, exhibiting both the properties of an activator domain and a transcriptional start site, and that the differential expression was directed by distinct repeat number in the VNTR. These properties embedded in the VNTR demonstrated the potential for this VNTR to modulate CFAP410 expression. We extrapolated these findings in silico by utilisation of tagging SNPs for the two most common VNTR alleles to establish a correlation with endogenous gene expression. Consistent with in vitro data, CFAP410 isoform expression was found to be variable in the brain. Furthermore, although the number of matched controls was low, there was evidence for one specific isoform being correlated with lower expression in those with ALS. To address if the genotype of the VNTR was associated with ALS risk, we characterised the variation of the CFAP410 VNTR in ALS cases and matched controls by PCR analysis of the VNTR length, defining eight alleles of the VNTR. No significant difference was observed between cases and controls, we noted, however, the cohort was unlikely to contain sufficient power to enable any firm conclusion to be drawn from this analysis. This data demonstrated that the VNTR domain has the potential to modulate CFAP410 expression as a regulatory element that could play a role in its tissue-specific and stimulus-inducible regulation that could impact the mechanism by which CFAP410 is involved in ALS. Frontiers Media S.A. 2022-09-05 /pmc/articles/PMC9484465/ /pubmed/36131690 http://dx.doi.org/10.3389/fnmol.2022.954928 Text en Copyright © 2022 Marshall, Fröhlich, Li, Pfaff, Middlehurst, Spargo, Iacoangeli, Lang, Al-Chalabi, Koks, Bubb and Quinn. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Neuroscience
Marshall, Jack N. G.
Fröhlich, Alexander
Li, Li
Pfaff, Abigail L.
Middlehurst, Ben
Spargo, Thomas P.
Iacoangeli, Alfredo
Lang, Bing
Al-Chalabi, Ammar
Koks, Sulev
Bubb, Vivien J.
Quinn, John P.
A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression
title A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression
title_full A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression
title_fullStr A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression
title_full_unstemmed A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression
title_short A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression
title_sort polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene cfap410 correlates with differential isoform expression
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484465/
https://www.ncbi.nlm.nih.gov/pubmed/36131690
http://dx.doi.org/10.3389/fnmol.2022.954928
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