Functional characterisation of a multiple sclerosis-associated genetic variant
<p>In recent years, Genome-wide association studies (GWAS) have identified several susceptibility-modifying genetic variants to complex diseases such as multiple sclerosis (MS). An association for one such single nucleotide polymorphism (SNP) in the gene encoding the principle receptor for the...
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| Format: | Thesis |
| Language: | English |
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2012
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| _version_ | 1797061496113463296 |
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| author | Gregory, A |
| author2 | Fugger, L |
| author_facet | Fugger, L Gregory, A |
| author_sort | Gregory, A |
| collection | OXFORD |
| description | <p>In recent years, Genome-wide association studies (GWAS) have identified several susceptibility-modifying genetic variants to complex diseases such as multiple sclerosis (MS). An association for one such single nucleotide polymorphism (SNP) in the gene encoding the principle receptor for the cytokine TNF (TNFR1), TNFRSF1A, has been replicated several times since its initial identification by De Jager et al., 2009. This study demonstrates that the MS risk-associated G allele of this SNP, rs1800693, results in an alternative splicing event in which exon 6 is excluded from the mature TNFRSF1A transcript both in an <em>in vitro</em> splicing assay and <em>ex vivo</em> in several human immune cell types, and investigates the potential for creating an antisense-based mouse model for the effect of this SNP. Importantly, we show that the transcript lacking exon 6 is translated into protein, designated Δ6TNFR1, which can be detected in primary samples. Δ6TNFR1 is truncated in several important domains of the full-length receptor and is demonstrated to be unable to traffick to and anchor at the cell membrane, instead being constitutively secreted. Moreover, in contrast with the full-length receptor, the MS-associated splice isoform is unable to oligomerise either homotypically or with full-length receptors, or to engage the NF-κB-mediated or apoptosis signalling pathways <em>in vitro</em>. Δ6TNFR1 does, however, retain the ability to bind and neutralise TNF, albeit to a lesser extent than the full-length protein. This is striking in light of the results of clinical trials for the use of TNF antagonists in MS patients, in which neutralisation of TNF was associated with relapses and exacerbation of symptoms, and rare MS symptom-like side-effects in patients being treated with anti-TNF agents for the management of other inflammatory autoimmune diseases. In conclusion, this work provides a functional explanation for the association of an MS-risk SNP with the disease and provides support for a detrimental effect of broad-spectrum TNF inhibition in MS. Moreover, it reveals a novel use for GWAS; to inform clinical practice.</p> |
| first_indexed | 2024-03-06T20:32:00Z |
| format | Thesis |
| id | oxford-uuid:315e39e4-548f-430b-8d54-68094c340a73 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:32:00Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:315e39e4-548f-430b-8d54-68094c340a732022-03-26T13:07:27ZFunctional characterisation of a multiple sclerosis-associated genetic variantThesishttp://purl.org/coar/resource_type/c_db06uuid:315e39e4-548f-430b-8d54-68094c340a73NeuroscienceLife SciencesClinical geneticsGenetics (life sciences)Medical SciencesGene medicineMultiple SclerosisBiology (medical sciences)ImmunologyGenetics (medical sciences)Medical sciencesBiologyEnglish2012Gregory, AFugger, L<p>In recent years, Genome-wide association studies (GWAS) have identified several susceptibility-modifying genetic variants to complex diseases such as multiple sclerosis (MS). An association for one such single nucleotide polymorphism (SNP) in the gene encoding the principle receptor for the cytokine TNF (TNFR1), TNFRSF1A, has been replicated several times since its initial identification by De Jager et al., 2009. This study demonstrates that the MS risk-associated G allele of this SNP, rs1800693, results in an alternative splicing event in which exon 6 is excluded from the mature TNFRSF1A transcript both in an <em>in vitro</em> splicing assay and <em>ex vivo</em> in several human immune cell types, and investigates the potential for creating an antisense-based mouse model for the effect of this SNP. Importantly, we show that the transcript lacking exon 6 is translated into protein, designated Δ6TNFR1, which can be detected in primary samples. Δ6TNFR1 is truncated in several important domains of the full-length receptor and is demonstrated to be unable to traffick to and anchor at the cell membrane, instead being constitutively secreted. Moreover, in contrast with the full-length receptor, the MS-associated splice isoform is unable to oligomerise either homotypically or with full-length receptors, or to engage the NF-κB-mediated or apoptosis signalling pathways <em>in vitro</em>. Δ6TNFR1 does, however, retain the ability to bind and neutralise TNF, albeit to a lesser extent than the full-length protein. This is striking in light of the results of clinical trials for the use of TNF antagonists in MS patients, in which neutralisation of TNF was associated with relapses and exacerbation of symptoms, and rare MS symptom-like side-effects in patients being treated with anti-TNF agents for the management of other inflammatory autoimmune diseases. In conclusion, this work provides a functional explanation for the association of an MS-risk SNP with the disease and provides support for a detrimental effect of broad-spectrum TNF inhibition in MS. Moreover, it reveals a novel use for GWAS; to inform clinical practice.</p> |
| spellingShingle | Neuroscience Life Sciences Clinical genetics Genetics (life sciences) Medical Sciences Gene medicine Multiple Sclerosis Biology (medical sciences) Immunology Genetics (medical sciences) Medical sciences Biology Gregory, A Functional characterisation of a multiple sclerosis-associated genetic variant |
| title | Functional characterisation of a multiple sclerosis-associated genetic variant |
| title_full | Functional characterisation of a multiple sclerosis-associated genetic variant |
| title_fullStr | Functional characterisation of a multiple sclerosis-associated genetic variant |
| title_full_unstemmed | Functional characterisation of a multiple sclerosis-associated genetic variant |
| title_short | Functional characterisation of a multiple sclerosis-associated genetic variant |
| title_sort | functional characterisation of a multiple sclerosis associated genetic variant |
| topic | Neuroscience Life Sciences Clinical genetics Genetics (life sciences) Medical Sciences Gene medicine Multiple Sclerosis Biology (medical sciences) Immunology Genetics (medical sciences) Medical sciences Biology |
| work_keys_str_mv | AT gregorya functionalcharacterisationofamultiplesclerosisassociatedgeneticvariant |