Allelic variation in the Tyk2 and EGF genes as potential genetic determinants of CNS repair

Allan J. Bieber, Kanitta Suwansrinon, Jason Kerkvliet, Weidong Zhang, Larry R. Pease, Moses Rodriguez

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The potential for endogenous remyelination and axonal protection can be an important factor in determining disease outcome in demyelinating diseases like multiple sclerosis. In many multiple sclerosis (MS) patients CNS repair fails or is incomplete whereas in others the disease is accompanied by extensive repair of demyelinated lesions.We have described significant differences in the ability of two strains ofmice to repair CNS damage following Theiler's virusinduced demyelination: FVB/NJ (FVB) mice repair damaged myelin spontaneously and completely,whereas B10.D1-H2q/SgJ (B10.Q)mice are deficient in the repair process. A QTL analysis was performed to identify genetic loci that differentially regulate CNS repair following chronic demyelination in these strains and two QTL were detected: one on chromosome 3 with a LOD score of 9.3 and a second on chromosome 9 with a LOD score of 14.0. The mouse genes for epidermal growth factor (EGF) and Tyk2 are encodedwithin the QTL on chromosomes 3 and 9, respectively. Sequence polymorphisms between the FVB and B10.Q strains at both the EGF and Tyk2 loci define functional variations consistent with roles for these genes in regulating myelin repair. EGF is a key regulator of cell growth and development andwe showa sevenfoldincrease inEGFexpressioninFVBcompared toB10.Q mice. Tyk2 is a Janus kinase that plays a central role in controlling the TH1 immune response and we show that attenuation of Tyk2 function correlates with enhanced CNS repair.

Original languageEnglish (US)
Pages (from-to)792-797
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number2
DOIs
StatePublished - 2010

Keywords

  • Multiple sclerosis
  • Quantitative trait locus
  • Remyelination
  • Theiler's murine encephalomyelitis virus

ASJC Scopus subject areas

  • General

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