A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene <i>CFAP410</i> correlates with differential isoform expression.


Marshall, Jack NG, Fröhlich, Alexander, Li, Li, Pfaff, Abigail L, Middlehurst, Ben, Spargo, Thomas P, Iacoangeli, Alfredo, Lang, Bing, Al-Chalabi, Ammar, Koks, Sulev ORCID: 0000-0001-6087-6643 et al (show 2 more authors) (2022) A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene <i>CFAP410</i> correlates with differential isoform expression. Frontiers in molecular neuroscience, 15. p. 954928.

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Abstract

We describe the characterisation of a variable number tandem repeat (VNTR) domain within intron 1 of the amyotrophic lateral sclerosis (ALS) risk gene <i>CFAP410</i> (<i>Cilia and flagella associated protein 410</i>) (previously known as <i>C21orf2</i>), 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 <i>CFAP410</i> expression. We extrapolated these findings <i>in silico</i> by utilisation of tagging SNPs for the two most common VNTR alleles to establish a correlation with endogenous gene expression. Consistent with <i>in vitro</i> data, <i>CFAP410</i> 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 <i>CFAP410</i> 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 <i>CFAP410</i> 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 <i>CFAP410</i> is involved in ALS.

Item Type: Article
Uncontrolled Keywords: CFAP410, ALS, VNTR, gene expression, transcriptional regulation
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 Oct 2022 10:22
Last Modified: 18 Jan 2023 20:41
DOI: 10.3389/fnmol.2022.954928
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3165095
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