Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis

• DOI: 10.1038/ncomms1333
• Publication Date: 2011-05-31T08:50:12Z
• Authors: Haik Mkhikian; Ani Grigorian; Carey F. Li; Hung-Lin Chen; Barbara Newton; Raymond W. Zhou; Christine Beeton; Sevan Torossian; Gevork Grikor Tat...; Sung-Uk Lee; Ken Lau; Erin Walker; Katherine A. Simi...; K. George Chandy; Zhaoxia Yu; James W. Dennis; Michael Demetriou
• Keywords: CTLA-4; Pleiotropy

How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, latter pathologies characteristic of MS. Here we show that MS modulators converge alter N-glycosylation CTLA-4 surface retention conditional on metabolism vitamin D3, including variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 (IL2RA*T), MGAT1 (IVAVT−T) (Thr17Ala). Downregulation IL7RA*C IL2RA*T opposed optimizing mitigating when combined enhanced Thr17. Our data suggest a mechanism whereby inputs lead dysregulation final common pathway, namely N-glycosylation. Complex have both components. This study demonstrates genes implicated sclerosis, alterations cellular D3 levels, alterN-glycosylation, post-translational modification causal disease mice.