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Advanced intercross line mapping of Eae5 reveals Ncf-1 and CLDN4 as candidate genes for experimental autoimmune encephalomyelitis

Becanovic, K ; Jagodic, M ; Sheng, JR ; Dahlman, I ; Aboul-Enein, F ; Wallstrom, E ; Olofsson, P ; Holmdahl, Rikard LU ; Lassmann, H and Olsson, T (2006) In Journal of Immunology 176(10). p.6055-6064
Abstract
Eae5 in rats was originally identified in two F-2 intercrosses, (DA x BN) and (E3 X DA), displaying linkage to CNS inflammation and disease severity in experimental autoimmune encephalomyelitis (EAE), respectively. This region overlaps with an arthritis locus, Pia4, which was also identified in the (E3 X DA) cross. Two congenic strains, BN.DA-Eae5 and BN.DA-Eae5.R1, encompassing the previously described Eae5 and Pia4, were established. DA alleles within the chromosome 12 fragment conferred an increase in disease susceptibility as well as increased inflammation and demyelination in the CNS as compared with BN alleles. To enable a more precise fine mapping of EAE regulatory genes, we used a rat advanced intercross line between the... (More)
Eae5 in rats was originally identified in two F-2 intercrosses, (DA x BN) and (E3 X DA), displaying linkage to CNS inflammation and disease severity in experimental autoimmune encephalomyelitis (EAE), respectively. This region overlaps with an arthritis locus, Pia4, which was also identified in the (E3 X DA) cross. Two congenic strains, BN.DA-Eae5 and BN.DA-Eae5.R1, encompassing the previously described Eae5 and Pia4, were established. DA alleles within the chromosome 12 fragment conferred an increase in disease susceptibility as well as increased inflammation and demyelination in the CNS as compared with BN alleles. To enable a more precise fine mapping of EAE regulatory genes, we used a rat advanced intercross line between the EAE-susceptible DA strain and the EAE-resistant PVG.1AV1 strain. Linkage analysis performed in the advanced intercross line considerably narrowed down the myelin oligodendrocyte glycoprotein-EAE regulatory locus (Eae5) to a similar to 1.3-megabase region with a defined number of candidate genes. In this study we demonstrate a regulatory effect of Eae5 on MOG-EAE by using both congenic strains as well as fine mapping these effects to a region containing Ncf-1, a gene associated with arthritis. In addition to structural polymorphisms in Ncf-1, both sequence polymorphisms and expression differences were identified in CLDN4. CLDN4 is a tight junction protein involved in blood-brain barrier integrity. In conclusion, our data strongly suggests Ncf-1 to be a gene shared between two organ-specific inflammatory diseases with a possible contribution by CLDN4 in encephalomyelitis. (Less)
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Contribution to journal
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published
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in
Journal of Immunology
volume
176
issue
10
pages
6055 - 6064
publisher
American Association of Immunologists
external identifiers
  • pmid:16670314
  • wos:000237705200044
  • scopus:33646493351
ISSN
1550-6606
language
English
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yes
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The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)
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501c8717-a9b9-48cb-8d7d-4d4d67213496 (old id 408607)
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http://www.jimmunol.org/cgi/content/abstract/176/10/6055
date added to LUP
2016-04-01 15:19:21
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2020-05-13 03:22:03
@article{501c8717-a9b9-48cb-8d7d-4d4d67213496,
  abstract     = {Eae5 in rats was originally identified in two F-2 intercrosses, (DA x BN) and (E3 X DA), displaying linkage to CNS inflammation and disease severity in experimental autoimmune encephalomyelitis (EAE), respectively. This region overlaps with an arthritis locus, Pia4, which was also identified in the (E3 X DA) cross. Two congenic strains, BN.DA-Eae5 and BN.DA-Eae5.R1, encompassing the previously described Eae5 and Pia4, were established. DA alleles within the chromosome 12 fragment conferred an increase in disease susceptibility as well as increased inflammation and demyelination in the CNS as compared with BN alleles. To enable a more precise fine mapping of EAE regulatory genes, we used a rat advanced intercross line between the EAE-susceptible DA strain and the EAE-resistant PVG.1AV1 strain. Linkage analysis performed in the advanced intercross line considerably narrowed down the myelin oligodendrocyte glycoprotein-EAE regulatory locus (Eae5) to a similar to 1.3-megabase region with a defined number of candidate genes. In this study we demonstrate a regulatory effect of Eae5 on MOG-EAE by using both congenic strains as well as fine mapping these effects to a region containing Ncf-1, a gene associated with arthritis. In addition to structural polymorphisms in Ncf-1, both sequence polymorphisms and expression differences were identified in CLDN4. CLDN4 is a tight junction protein involved in blood-brain barrier integrity. In conclusion, our data strongly suggests Ncf-1 to be a gene shared between two organ-specific inflammatory diseases with a possible contribution by CLDN4 in encephalomyelitis.},
  author       = {Becanovic, K and Jagodic, M and Sheng, JR and Dahlman, I and Aboul-Enein, F and Wallstrom, E and Olofsson, P and Holmdahl, Rikard and Lassmann, H and Olsson, T},
  issn         = {1550-6606},
  language     = {eng},
  number       = {10},
  pages        = {6055--6064},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Advanced intercross line mapping of Eae5 reveals Ncf-1 and CLDN4 as candidate genes for experimental autoimmune encephalomyelitis},
  url          = {http://www.jimmunol.org/cgi/content/abstract/176/10/6055},
  volume       = {176},
  year         = {2006},
}