Hypomorphic MGAT5 Polymorphisms Promote Multiple Sclerosis Cooperatively With MGAT1 and interleukin-2 and 7 Receptor Variants

J Neuroimmunol. 2013 Mar 15;256(1-2):71-6. doi: 10.1016/j.jneuroim.2012.12.008. Epub 2013 Jan 22.


Deficiency of the Golgi N-glycan branching enzyme Mgat5 in mice promotes T cell hyperactivity, endocytosis of CTLA-4 and autoimmunity, including a spontaneous multiple sclerosis (MS)-like disease. Multiple genetic and environmental MS risk factors lower N-glycan branching in T cells. These include variants in interleukin-2 receptor-α (IL2RA), interleukin-7 receptor-α (IL7RA), and MGAT1, a Golgi branching enzyme upstream of MGAT5, as well as vitamin D3 deficiency and Golgi substrate metabolism. Here we describe linked intronic variants of MGAT5 that are associated with reduced N-glycan branching, CTLA-4 surface expression and MS (p=5.79×10(-9), n=7,741), the latter additive with the MGAT1, IL2RA and IL7RA MS risk variants (p=1.76×10(-9), OR=0.67-1.83, n=3,518).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CTLA-4 Antigen / metabolism
  • Case-Control Studies
  • Cohort Studies
  • Down-Regulation
  • Female
  • Flow Cytometry
  • Galactosyltransferases / genetics
  • Galactosyltransferases / metabolism
  • Genetic Variation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / pathology
  • N-Acetylglucosaminyltransferases / genetics*
  • N-Acetylglucosaminyltransferases / metabolism
  • Receptors, Interleukin-2 / genetics*
  • Receptors, Interleukin-7 / genetics*
  • Risk Factors
  • T-Lymphocytes / metabolism
  • Young Adult


  • CTLA-4 Antigen
  • Receptors, Interleukin-2
  • Receptors, Interleukin-7
  • Galactosyltransferases
  • N-Acetylglucosaminyltransferases