Abstract
The MBL1 and MBL2 genes encode mannan-binding lectins (MBL) A and C, respectively, that are collagenous lectins (collectins) produced mainly by the liver. Several single-nucleotide polymorphisms (SNPs) in the human MBL2 gene are responsible for various innate immune dysfunctions due to abnormal structure or expression of human MBL-C. The MBL1 gene encodes MBL-A, which has bacteria-binding properties in pigs and rodents but is mutated to a pseudogene in humans and chimpanzees. In these studies, we surveyed both porcine MBL genes for SNPs that might impair disease resistance. Single-strand conformational polymorphism (SSCP) analysis of MBL cDNAs from porcine liver revealed three SNPs within the coding region of MBL1 in various breeds of pigs. One nonsynonymous SNP that substituted cysteine for glycine in the collagen-like domain of pig MBL-A was found by a multiplex PCR test in all European pig breeds examined, with allele frequencies ranging from 1.4 to 46.4%. No SNPs were identified in the coding region of porcine MBL2 but the expression of MBL-C in the liver was widely variable in comparison to the expression of MBL-A, GAPDH, PigMAP, and haptoglobin. These results indicate that some pigs have a miscoding defect in MBL-A and a possible expression defect in MBL-C, which are analogous to coding and promoter polymorphisms that affect human MBL-C.






Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.Abbreviations
- MBL:
-
mannan-binding lectin
- SNP:
-
single-nucleotide polymorphism
- SSCP:
-
single-strand conformational polymorphism
- MASP:
-
MBL-associated serine protease
- sMAP:
-
small MBL-associated protein
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- PigMAP:
-
pig major acute-phase protein
References
Agah A, Montalto MC, Young K, Stahl GL (2001) Isolation, cloning and functional characterization of porcine mannose- binding lectin. Immunology 102:338–343
Arora M, Munoz E, Tenner AJ (2001) Identification of a site on mannan-binding lectin critical for enhancement of phagocytosis. J Biol Chem 276:43087–43094
Brooks AS, DeLay JP, Hayes MA (2003) Characterization of porcine plasma ficolins that bind Actinobacillus pleuropneumoniae serotype 5B. Immunobiology 207:327–337
Butler GS, Sim D, Tam E, Devine D, Overall CM (2002) Mannose-binding lectin (MBL) mutants are susceptible to matrix metalloproteinase proteolysis: potential role in human MBL deficiency. J Biol Chem 277:17511–17519
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159
Crouch E, Persson A, Chang D, Heuser J (1994) Molecular structure of pulmonary surfactant protein D (SP-D). J Biol Chem 269:17311–17319
Eisen DP, Minchinton RM (2003) Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis 37:1496–1505
Ezekowitz RA, Day LE, Herman GA (1988) A human mannose-binding protein is an acute-phase reactant that shares sequence homology with other vertebrate lectins. J Exp Med 167:1034–1046
Gabolde M, Guilloud-Bataille M, Feingold J, Besmond C (1999) Association of variant alleles of mannose binding lectin with severity of pulmonary disease in cystic fibrosis: cohort study. BMJ 319:1166–1167
Gadjeva M, Paludan SR, Thiel S, Slavov V, Ruseva M, Eriksson K, Lowhagen GB, Shi L, Takahashi K, Ezekowitz A, Jensenius JC (2004) Mannan-binding lectin modulates the response to HSV-2 infection. Clin Exp Immunol 138:304–311
Garred P, Madsen HO, Balslev U, Hofmann B, Pedersen C, Gerstoft J, Svejgaard A (1997) Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin. Lancet 349:236–240
Garred P, Larsen F, Madsen HO, Koch C (2003) Mannose-binding lectin deficiency-revisited. Mol Immunol 40:73–84
Garred P, Larsen F, Seyfarth J, Fujita R, Madsen HO (2006) Mannose-binding lectin and its genetic variants. Genes Immun 7:85–94
Gonzalez-Ramon N, Hoebe K, Alava MA, Van Leengoed L, Pineiro M, Carmona S, Iturralde M, Lampreave F, Pineiro A (2000) Pig MAP/ITIH4 and haptoglobin are interleukin-6-dependent acute-phase plasma proteins in porcine primary cultured hepatocytes. Eur J Biochem 267:1878–1885
Guo N, Mogues T, Weremowicz S, Morton CC, Sastry KN (1998) The human ortholog of rhesus mannose-binding protein-A gene is an expressed pseudogene that localizes to chromosome 10. Mamm Genome 9:246–249
Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA (1999) Phylogenetic perspectives in innate immunity. Science 284:1313–1318
Holmskov U, Laursen SB, Malhotra R, Wiedemann H, Timpl R, Stuart GR, Tornoe I, Madsen PS, Reid KB, Jensenius JC (1995) Comparative study of the structural and functional properties of a bovine plasma C-type lectin, collectin-43, with other collectins. Biochem J 305(Pt 3):889–896
Holmskov U, Thiel S, Jensenius JC (2003) Collectins and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol 21:547–578
Jack DL, Turner MW (2003) Anti-microbial activities of mannose-binding lectin. Biochem Soc Trans 31:753–757
Jordan JE, Montalto MC, Stahl GL (2001) Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury. Circulation 104:1413–1418
Juul-Madsen HR, Krogh-Meibom T, Henryon M, Palaniyar N, Heegaard PM, Purup S, Willis AC, Tornoe I, Ingvartsen KL, Hansen S, Holmskov U (2006) Identification and characterization of porcine mannan-binding lectin A (pMBL-A), and determination of serum concentration heritability. Immunogenetics 58:129–137
Kase T, Suzuki Y, Kawai T, Sakamoto T, Ohtani K, Eda S, Maeda A, Okuno Y, Kurimura T, Wakamiya N (1999) Human mannan-binding lectin inhibits the infection of influenza A virus without complement. Immunology 97:385–392
Larsen F, Madsen HO, Sim RB, Koch C, Garred P (2004) Disease-associated mutations in human mannose-binding lectin compromise oligomerization and activity of the final protein. J Biol Chem 279:21302–21311
Lee SJ, Gonzalez-Aseguinolaza G, Nussenzweig MC (2002) Disseminated candidiasis and hepatic malarial infection in mannose-binding-lectin-A-deficient mice. Mol Cell Biol 22:8199–8203
Lillie BN, Brooks AS, Keirstead ND, Hayes MA (2005) Comparative genetics and innate immune functions of collagenous lectins in animals. Vet Immunol Immunopathol 108:97–110
Lillie BN, Hammermueller JD, MacInnes JI, Jacques M, Hayes MA (2006) Porcine mannan-binding lectin A binds to Actinobacillus suis and Haemophilus parasuis. Dev Comp Immunol 30:954–965
Lin Z, Lou Y, Peacock J, Squires EJ (2005) A novel polymorphism in the 5′ untranslated region of the porcine cytochrome b5 (CYB5) gene is associated with decreased fat androstenone level. Mamm Genome 16:367–373
Lipscombe RJ, Sumiya M, Hill AV, Lau YL, Levinsky RJ, Summerfield JA, Turner MW (1992) High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene. Hum Mol Genet 1:709–715
Madsen HO, Garred P, Kurtzhals JA, Lamm LU, Ryder LP, Thiel S, Svejgaard A (1994) A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein. Immunogenetics 40:37–44
Madsen HO, Garred P, Thiel S, Kurtzhals JA, Lamm LU, Ryder LP, Svejgaard A (1995) Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol 155:3013–3020
Madsen HO, Satz ML, Hogh B, Svejgaard A, Garred P (1998) Different molecular events result in low protein levels of mannan-binding lectin in populations from southeast Africa and South America. J Immunol 161:3169–3175
Marklund L, Shi X, Tuggle CK (2000) Rapid communication: mapping of the Mannose-Binding Lectin 2 (MBL2) gene to pig chromosome 14. J Anim Sci 78:2992–2993
Matsushita M (1996) The lectin pathway of the complement system. Microbiol Immunol 40:887–893
Matsushita M, Endo Y, Hamasaki N, Fujita T (2001) Activation of the lectin complement pathway by ficolins. Int Immunopharmacol 1:359–363
Moller-Kristensen M, Ip WK, Shi L, Gowda LD, Hamblin MR, Thiel S, Jensenius JC, Ezekowitz RA, Takahashi K (2006) Deficiency of mannose-binding lectin greatly increases susceptibility to postburn infection with Pseudomonas aeruginosa. J Immunol 176:1769–1775
Nielsen OL, Jensenius JC, Jorgensen PH, Laursen SB (1999) Serum levels of chicken mannan-binding lectin (MBL) during virus infections; indication that chicken MBL is an acute phase reactant. Vet Immunol Immunopathol 70:309–316
Saevarsdottir S, Vikingsdottir T, Vikingsson A, Manfredsdottir V, Geirsson AJ, Valdimarsson H (2001) Low mannose binding lectin predicts poor prognosis in patients with early rheumatoid arthritis. A prospective study. J Rheumatol 28:728–734
Sastry R, Wang JS, Brown DC, Ezekowitz RA, Tauber AI, Sastry KN (1995) Characterization of murine mannose-binding protein genes Mbl1 and Mbl2 reveals features common to other collectin genes. Mamm Genome 6:103–110
Seyfarth J, Garred P, Madsen HO (2005) The ‘involution’ of mannose-binding lectin. Hum Mol Genet 14:2859–2869
Shi L, Takahashi K, Dundee J, Shahroor-Karni S, Thiel S, Jensenius JC, Gad F, Hamblin MR, Sastry KN, Ezekowitz RA (2004) Mannose-binding lectin-deficient mice are susceptible to infection with Staphylococcus aureus. J Exp Med 199:1379–1390
Sorensen R, Thiel S, Jensenius JC (2005) Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. Springer Semin Immunopathol 27:299–319
Storgaard P, Nielsen EH, Andersen O, Skriver E, Mortensen H, Hojrup P, Leslie G, Holmskow U, Svehag SE (1996) Isolation and characterization of porcine mannan-binding proteins of different size and ultrastructure. Scand J Immunol 43:289–296
Sumiya M, Super M, Tabona P, Levinsky RJ, Arai T, Turner MW, Summerfield JA (1991) Molecular basis of opsonic defect in immunodeficient children. Lancet 337:1569–1570
Takahashi K, Gordon J, Liu H, Sastry KN, Epstein JE, Motwani M, Laursen I, Thiel S, Jensenius JC, Carroll M, Ezekowitz RA (2002) Lack of mannose-binding lectin-A enhances survival in a mouse model of acute septic peritonitis. Microbes Infect 4:773–784
Takahashi R, Tsutsumi A, Ohtani K, Muraki Y, Goto D, Matsumoto I, Wakamiya N, Sumida T (2005) Association of mannose binding lectin (MBL) gene polymorphism and serum MBL concentration with characteristics and progression of systemic lupus erythematosus. Ann Rheum Dis 64:311–314
Thiel S, Holmskov U, Hviid L, Laursen SB, Jensenius JC (1992) The concentration of the C-type lectin, mannan-binding protein, in human plasma increases during an acute phase response. Clin Exp Immunol 90:31–35
Thiel S, Petersen SV, Vorup-Jensen T, Matsushita M, Fujita T, Stover CM, Schwaeble WJ, Jensenius JC (2000) Interaction of C1q and mannan-binding lectin (MBL) with C1r, C1s, MBL-associated serine proteases 1 and 2, and the MBL-associated protein MAp19. J Immunol 165:878–887
Thielens NM, Tacnet-Delorme P, Arlaud GJ (2002) Interaction of C1q and mannan-binding lectin with viruses. Immunobiology 205:563–574
van de Wetering JK, van Golde LM, Batenburg JJ (2004) Collectins: players of the innate immune system. Eur J Biochem 271:1229–1249
Wallis R (2002a) Dominant effects of mutations in the collagenous domain of mannose-binding protein. J Immunol 168:4553–4558
Wallis R (2002b) Structural and functional aspects of complement activation by mannose-binding protein. Immunobiology 205:433–445
Wallis R, Cheng JY (1999) Molecular defects in variant forms of mannose-binding protein associated with immunodeficiency. J Immunol 163:4953–4959
Wallis R, Drickamer K (1999) Molecular determinants of oligomer formation and complement fixation in mannose-binding proteins. J Biol Chem 274:3580–3589
Wallis R, Shaw JM, Uitdehaag J, Chen CB, Torgersen D, Drickamer K (2004) Localization of the serine protease-binding sites in the collagen-like domain of mannose-binding protein: indirect effects of naturally occurring mutations on protease binding and activation. J Biol Chem 279:14065–14073
Ye S, Dhillon S, Ke X, Collins AR, Day IN (2001) An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res 29:E88
Acknowledgments
We appreciate the assistance of Andrew Brooks, Janet MacInnes, Mario Jacques, Bette Anne Quinn, Yanping Lou, John Peacock, Lilly Bojarski, and Alex Loretti. The pathologists at the Animal Health Laboratory, especially Josepha Delay and Beverly McEwen, as well as Robert Friendship, were instrumental in the collection of the diseased pig tissue samples. Funding from the Canadian Research Network on Bacterial Pathogens of Swine, the Natural Sciences and Engineering Research Council of Canada (NSERC), Ontario Pork, the Ontario Ministry of Agriculture and Food, and the Ontario Veterinary College supported this work.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lillie, B.N., Keirstead, N.D., Squires, E.J. et al. Single-nucleotide polymorphisms in porcine mannan-binding lectin A. Immunogenetics 58, 983–993 (2006). https://doi.org/10.1007/s00251-006-0160-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-006-0160-z