ClinVar

Gregory et al. (2012) investigated the contribution of the single-nucleotide polymorphism (SNP) rs1800693 to susceptibility to multiple sclerosis associated with the TNFRSF1A region (MS5; 614810). The SNP rs1800693 is proximal to the TNFRSF1A exon 6/intron 6 boundary, and the G risk allele resulted in skipping of exon 6 in minigene splicing assays. In primary human immune cells, the presence of the risk allele correlated with increased expression of transcripts lacking exon 6. TNFR1 exon 6 skipping results in a frameshift and a premature stop codon, which translates into a protein comprising only the amino-terminal 183 amino acids of TNFR1 followed by a novel 45 amino acid sequence, as confirmed by tandem mass spectrometry. This mutant protein, delta-6-TNFR1, lacks the extracellular carboxy-terminal portion of the fourth cysteine-rich domain of the select protein, the transmembrane domain, and the intracellular region that is essential for appropriate subcellular localization. The mutant protein demonstrated a more diffuse intracellular distribution than the normal localization to the Golgi apparatus. Gregory et al. (2012) found no significant spontaneous NF-kappa-B (see 164011) signaling or TNFR1-mediated apoptosis upon delta-6-TNFR1 expression. However, the mutant protein could potentially retain some intracellular activity by accumulating in the endoplasmic reticulum and evoking a stress response. Gregory et al. (2012) concluded that the combined genetic and functional analyses strongly implicated rs1800693 as the causal SNP in the MS-associated TNFRSF1A region. Because the delta-6-TNFR1 protein is soluble and capable of TNF antagonism, Gregory et al. (2012) concluded that their evidence was consistent with the reported worsening of MS upon anti-TNF therapy.