Novel Insights into the Multiple Sclerosis Risk Gene ANKRD55

Abstract

An intronic variant in ANKRD55, rs6859219, is a genetic risk factor for multiple sclerosis, but the biological reasons underlying this association are unknown. We characterized the expression of ANKRD55 in human PBMCs and cell lines. Three ANKRD55 transcript variants (Ensembl isoforms 001, 005, and 007) could be detected in PBMCs and CD4+ T cells but were virtually absent in CD8+, CD14+, CD19+, and CD56+ cells. Rs6859219 was significantly associated with ANKRD55 transcript levels in PBMCs and CD4+ T cells and, thus, coincides with a cis-expression quantitative trait locus. The processed noncoding transcript 007 was the most highly expressed variant in CD4+ T cells, followed by 001 and 005, respectively, but it was not detected in Jurkat, U937, and SH-SY5Y cell lines. Homozygotes for the risk allele produced more than four times more transcript copies than did those for the protective allele. ANKRD55 protein isoforms 005 and 001 were predominantly located in the nucleus of CD4+ T cells and Jurkat and U937 cells. ANKRD55 was produced by primary cultures of murine hippocampal neurons and microglia, as well as by the murine microglial cell line BV2, and it was induced by inflammatory stimuli. ANKRD55 protein was increased in the murine mouse model of experimental autoimmune encephalomyelitis. Flow cytometric analysis of CNS-infiltrating mononuclear cells showed that CD4+ T cells and monocytes expressed ANKRD55 in experimental autoimmune encephalomyelitis mice, with the higher fluorescence intensity found in CD4+ cells. A low percentage of microglia also expressed ANKRD55. Together, these data support an important role for ANKRD55 in multiple sclerosis and neuroinflammation.

Positive Association betweenANKRD55Polymorphism 7731626 and Dermatomyositis/Polymyositis with Interstitial Lung Disease in Chinese Han Population

“…However, these identified susceptibility genes do not fully account for the genetic pathogenesis of DM/PM-ILD. ANKRD55 has been shown to be inducible following inflammatory stimuli, and its expression may also increase susceptibility to inflammation in patients [29]. An increase in the protein expression of ANKRD55 in autoimmune encephalomyelitis mice suggests that this molecule may act as a disease biomarker.…”

“…ANKRD55 encodes ankyrin repeat domain-containing protein 55, which mediates protein-protein interactions. A recent report has revealed that ANKRD55 can be detected in resting CD4+ T cells and monocytes and may have possible relevance to autoimmune diseases (http://www.amazonia.transcriptome.eu) [29]. However, the exact function of ANKRD55 remains unknown.…”

Interactome of the Autoimmune Risk Protein ANKRD55

“…Further studies have underscored pleiotropy of ANKRD55 by linking SNPs in this locus to Crohn's Disease (7, 8), type 1 diabetes (9), juvenile idiopathic arthritis (10), celiac disease (11) and inflammatory myopathies (polymyositis and dermatomyositis) (12, 13), as well as post-traumatic stress disorder (14), cognitive decline in Alzheimer's disease (15), and type 2 diabetes (16, 17). Rs6859219 is significantly associated with expression levels of three ANKRD55 transcripts, i.e., Ensembl (GRCh37.p13 Human Genome Assembly) full-length protein isoform 001, shorter protein isoform 005 and non-coding transcript 007 in PBMCs, and 001 and 005 in CD4 + T cells (18), and acts thus as a cis-expression quantitative trait locus ( cis -eQTL). Rs71624119 (19) as wells as rs10065637 (20), a perfect proxy of rs6859219, were independently identified as cis -eQTLs for ANKRD55 expression, the latter so by means of multiple tagging probes.…”

“…Rs71624119 (19) as wells as rs10065637 (20), a perfect proxy of rs6859219, were independently identified as cis -eQTLs for ANKRD55 expression, the latter so by means of multiple tagging probes. The risk alleles of associated eQTL SNPs such as rs6859219, rs71624119 and rs10065637 are shared among autoimmune diseases and are associated with higher expression of ANKRD55 in CD4 + T lymphocytes (18–20). Thus, ANKRD55 appears as the nearest annotated gene affected by the risk eQTL SNP rs6859219 or its proxies that emerged from GWAS on various autoimmune diseases.…”

The era of GWAS is over – Yes

“…A portion of target genes affected by risk QTLs code for proteins with as yet unknown or poorly understood biological functions, such as ANKRD55; hence, clarification from scratch of the biology of sometimes multiple co-produced isoforms is required. 7 In MS, cellular targets to be scrutinized by combinations of these and other approaches not only include cells of the peripheral immune system, CD4 + T cells, and monocytes but also central nervous system (CNS)-resident cells such as microglia and activated astrocytes. [1][2][3] Thus, an elaborate and multipronged experimental design is needed to fully understand the biological repercussions of the causal variant starting from the associated variant.…”