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

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Jack N.G. Marshall, Alexander Fröhlich, Li Li, Abigail L. Pfaff, Ben Middlehurst, Thomas P. Spargo, Alfredo Iacoangeli, Bing Lang, Ammar Al-Chalabi, Sulev Koks, Vivien J. Bubb, John P. Quinn

Original languageEnglish
Article number954928
JournalFrontiers in Molecular Neuroscience
Volume15
DOIs
Published5 Sep 2022

Bibliographical note

Funding Information: Samples used in this research were obtained from the UK MND DNA Bank for ALS Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with ALS and their families for their participation in this project. We acknowledge the Target ALS Human Postmortem Tissue Core, New York Genome Centre for Genomics of Neurodegenerative Disease, Amyotrophic Lateral Sclerosis Association and TOW Foundation for RNA-seq data of human ALS patients. Funding Information: Samples used in this research were obtained from the UK MND DNA Bank for ALS Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with ALS and their families for their participation in this project. We acknowledge the Target ALS Human Postmortem Tissue Core, New York Genome Centre for Genomics of Neurodegenerative Disease, Amyotrophic Lateral Sclerosis Association and TOW Foundation for RNA-seq data of human ALS patients. Funding Information: JM was funded by a Medical Research Council Doctoral Training Studentship [Grant Number MR/N013840/1]. AF is a recipient of a Andrzej Wlodarski Memorial Research Ph.D. scholarship. Motor Neurone Disease Association (Grant Number: 41/523) supports the work of VB and JQ. AF, VB, and JQ by the Andrzej Wlodarski Memorial Research. BM, VB, and JQ are supported by the Darby Rimmer MND Foundation. LL was supported by the Chinese Scholarship Council 201806370099. SK and AP were supported by MSWA and Perron Institute. AA-C is an NIHR Senior Investigator (NIHR202421), also supported by an EU Joint Programme—Neurodegenerative Disease Research (JPND) project grant through the following funding organisations under the aegis of JPND– www.jpnd.eu [United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)] and through the Motor Neurone Disease Association, My Name'5 Doddie Foundation and Alan Davidson Foundation. This study represents an independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. This work was supported by resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. Publisher Copyright: Copyright © 2022 Marshall, Fröhlich, Li, Pfaff, Middlehurst, Spargo, Iacoangeli, Lang, Al-Chalabi, Koks, Bubb and Quinn.

King's Authors

Abstract

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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