Influence of polymorphisms in porcine NOD2 on ligand recognition

Kosuke Jozaki a), Hiroki Shinkai b,c), Maiko Tanaka-Matsuda b,c), Takeya Morozumi b,c),
Toshimi Matsumoto b,c), Daisuke Toki b,c), Naohiko Okumura b,c), Tomoko Eguchi-Ogawa b,d),
Chihiro Kojima-Shibata e), Hiroshi Kadowaki e), Eisaku Suzuki e), Yasuhiko Wada f), Hirohide Uenishi b,d)

a) United Graduate School of Agricultural Sciences, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan
b) Animal Genome Research Program, 446-1 Ippaizuka, Kamiyokoba, Tsukuba, Ibaraki 305-0854, Japan
c) Second Research Division, Institute of Society for Techno-innovation of Agriculture, Forestry and Fisheries, 446-1 Ippaizuka, Kamiyokoba, Tsukuba, Ibaraki 305-0854, Japan
d) Division of Animal Sciences, National Institute of Agrobiological Sciences, 2-1-2 Kannondai, Tsukuba, Ibaraki 305-8602, Japan
e) Miyagi Livestock Experimental Station, Miyagi Prefecture, 1 Hiwatashi, Minamizawa, Iwadeyama, Osaki, Miyagi 989-6445, Japan
f) Faculty of Agriculture, Saga University, 1 Honjo, Saga 840-8502, Japan


Nucleotide oligomerization domain 2 (NOD2) is a cytosolic pattern recognition receptor (PRR) that responds to muramyldipeptide (MDP), a component of peptidoglycans of Gram positive and negative bacteria. NOD2 is involved in the modulation of signaling pathways for other PRRs, such as Toll-like receptors. Polymorphisms in NOD2 may evoke bowel disorders, and human Crohn’s disease is significantly correlated with mis-sense insertion of the NOD2 gene. Such polymorphisms affecting ligand recognition in the NOD2 gene may also influence bowel flora in livestock, which is compromised by bowel diseases such as diarrhea. We investigated the functional variance of mis-sense polymorphisms in ligand recognition by porcine NOD2. The 1949T>C polymorphism, located in the region encoding the hinge domain of the molecule, notably diminished the functional response of porcine NOD2 to MDP. By comparison, the 2197A>C polymorphism, localized in the region corresponding to leucine-rich repeats, significantly augmented the response of porcine NOD2 to the ligand. The 1949C allele was rare among pig breeds, suggesting that this mutation is a disadvantage to pigs in their immune response to microbes. The 2197C allele, in contrast, was widely distributed among Western breeds and is most likely to be derived from wild boars in Asia. This is the first report of a causal relationship between molecular function and polymorphisms in PRRs in non-primate, non-rodent mammals. These findings suggest that the 2197C allele might confer an immune response advantage in modern pig breeds and may be a useful marker for breeding aimed at disease resistance in pigs.
                                               Molecular Immunology 47 (2009) 247-252

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