Novel Insights into the Multiple Sclerosis Risk Gene ANKRD55

Area of Science:

• Neuroimmunology
• Genetics
• Molecular Biology

Background:

• Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system.
• An intronic variant, rs6859219, in the ANKRD55 gene is a known genetic risk factor for MS.
• The biological mechanisms linking rs6859219 to MS pathogenesis remain unclear.

Purpose of the Study:

• To investigate the expression patterns of ANKRD55 in human and murine cells.
• To determine the relationship between the MS risk variant rs6859219 and ANKRD55 expression.
• To explore the role of ANKRD55 in neuroinflammation and experimental autoimmune encephalomyelitis (EAE).

Main Methods:

• Characterization of ANKRD55 transcript variants in human peripheral blood mononuclear cells (PBMCs) and various cell lines.
• Quantitative analysis of ANKRD55 expression in relation to rs6859219 genotype.
• Immunofluorescence and flow cytometry to assess ANKRD55 protein localization and expression in human and murine cells, including during EAE.
• Analysis of ANKRD55 expression in response to inflammatory stimuli.

Main Results:

• Three ANKRD55 transcript variants (001, 005, 007) were detected in human PBMCs and CD4(+) T cells, with variant 007 being the most abundant.
• The rs6859219 variant acts as a cis-expression quantitative trait locus (eQTL), significantly associated with ANKRD55 transcript levels in PBMCs and CD4(+) T cells.
• Risk allele homozygotes showed over fourfold higher ANKRD55 transcript levels compared to protective allele homozygotes.
• ANKRD55 protein isoforms were localized to the nucleus in CD4(+) T cells and other cell lines.
• ANKRD55 was expressed in murine neurons and microglia, induced by inflammatory stimuli, and elevated in EAE.
• CD4(+) T cells and monocytes infiltrating the CNS in EAE mice showed increased ANKRD55 expression.

Conclusions:

• ANKRD55 expression is cell-type specific, predominantly in CD4(+) T cells.
• The MS risk variant rs6859219 influences ANKRD55 expression levels in a cis-regulatory manner.
• These findings support a significant role for ANKRD55 in the pathogenesis of multiple sclerosis and neuroinflammation.