Abstract
Many of inflammatory diseases, including inflammatory arthritis, are multifactorial bases. The Ali18 semidominant mutation induced by N-ethyl-N-nitrosourea in the C3HeB/FeJ (C3H) genome causes spontaneous inflammation of peripheral limbs and elevated immunoglobulin E (IgE) levels in mice. Although the Ali18 locus was mapped to a single locus on chromosome 4, the arthritic phenotype of Ali18/+ mice was completely suppressed in F1 hybrid genetic backgrounds. To determine the chromosomal locations of the modifier loci affecting the severity of arthritis, an autosomal genome scan of 22 affected Ali18/+ F2 mice was conducted using C57BL/6J as a partner strain. Interestingly, regions on chromosomes 1 and 3 in C3H showed significant genetic interactions. Moreover, 174 N2 (backcross to Ali18/Ali18) and 267 F2 animals were used for measurement of arthritis scores and plasma IgE levels, and also for genotyping with 153 genome-wide single nucleotide polymorphism (SNP) markers. In N2 populations, two significant trait loci for arthritis scores on chromosomes 1 and 15 were detected. Although no significant scores were detected in F2 mice besides chromosome 4, a suggestive score was detected on chromosome 3. In addition, a two-dimensional genome scan using F2 identified five suggestive scores of chromosomal combinations, chromosomes 1 × 10, 2 × 6, 3 × 4, 4 × 9, and 6 × 15. No significant trait loci affecting IgE levels were detected in both N2 and F2 populations. Identification of the Ali18 modifier genes by further detailed analyses such as congenic strains and expression profiling may dissect molecular complexity in inflammatory diseases.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abe K, Fuchs H, Lisse T, Hans W, Hrabé de Angelis M (2006) New ENU-induced semidominant mutation, Ali18, causes inflammatory arthritis, dermatitis, and osteoporosis in the mouse. Mamm Genome 17:915–926
Abe K, Wechs S, Kalaydjiev S, Franz TJ, Busch DH et al (2008) Novel lymphocyte-independent mechanisms to initiate inflammatory arthritis via bone marrow-derived cells of Ali18 mutant mice. Rheumatology (Oxford) 47:292–300
Aberdam D, Galliano MF, Vailly J, Pulkkinen L, Bonifas J et al (1994) Herlitz’s junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma 2 subunit of nicein/kalinin (LAMININ-5). Nat Genet 6:299–304
Alessandrini F, Jakob T, Wolf A, Wolf E, Balling R et al (2001) ENU mouse mutagenesis: generation of mouse mutants with aberrant plasma IgE levels. Int Arch Allergy Immunol 124:25–28
Asagiri M, Hirai T, Kunigami T, Kamano S, Gober HJ et al (2008) Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science 319:624–627
Botstein D, Risch N (2003) Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 33(Suppl):228–237
Broman KW, Wu H, Sen S, Churchill GA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19:889–890
Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971
Fuchs H, Schughart K, Wolf E, Balling R, Hrabé de Angelis M (2000) Screening for dysmorphological abnormalities—a powerful tool to isolate new mouse mutants. Mamm Genome 11:528–530
Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236–1238
Gregersen PK, Behrens TW (2006) Genetics of autoimmune diseases—disorders of immune homeostasis. Nat Rev Genet 7:917–928
Hrabé de Angelis MH, Flaswinkel H, Fuchs H, Rathkolb B, Soewarto D et al (2000) Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nat Genet 25:444–447
Jakob T, Alessandrini F, Gutermuth J, Kšllisch G, Javaheri A et al (2006) Phenotyping allergy in laboratory mice. Wiley-VCH Verlag, Weinheim
Jakob T, Kollisch GV, Howaldt M, Bewersdorff M, Rathkolb B et al (2008) Novel mouse mutants with primary cellular immunodeficiencies generated by genome-wide mutagenesis. J Allergy Clin Immunol 121:179–184
Ji H, Gauguier D, Ohmura K, Gonzalez A, Duchatelle V et al (2001) Genetic influences on the end-stage effector phase of arthritis. J Exp Med 194:321–330
Joe B (2006) Quest for arthritis-causative genetic factors in the rat. Physiol Genomics 27:1–11
Kiernan AE, Li R, Hawes NL, Churchill GA, Gridley T (2007) Genetic background modifies inner ear and eye phenotypes of jag1 heterozygous mice. Genetics 177:307–311
Klaften M, Hrabé de Angelis M (2005) ARTS: a web-based tool for the set-up of high-throughput genome-wide mapping panels for the SNP genotyping of mouse mutants. Nucleic Acids Res 33:W496–W500
Kuida S, Beier DR (2000) Genetic localization of interacting modifiers affecting severity in a murine model of polycystic kidney disease. Genome Res 10:49–54
Matin A, Nadeau JH (2001) Sensitized polygenic trait analysis. Trends Genet 17:727–731
Nadeau JH, Topol EJ (2006) The genetics of health. Nat Genet 38:1095–1098
Robb L, Drinkwater CC, Metcalf D, Li R, Kontgen F et al (1995) Hematopoietic and lung abnormalities in mice with a null mutation of the common beta subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5. Proc Natl Acad Sci U S A 92:9565–9569
Rubio-Aliaga I, Soewarto D, Wagner S, Klaften M, Fuchs H et al (2007) A genetic screen for modifiers of the delta1-dependent notch signaling function in the mouse. Genetics 175:1451–1463
Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A et al (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A 95:13453–13458
Sen S, Churchill GA (2001) A statistical framework for quantitative trait mapping. Genetics 159:371–387
Soewarto D, Fella C, Teubner A, Rathkolb B, Pargent W et al (2000) The large-scale Munich ENU-mouse-mutagenesis screen. Mamm Genome 11:507–510
Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E et al (1995) Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268:1472–1476
Vidal S, Kono DH, Theofilopoulos AN (1998) Loci predisposing to autoimmunity in MRL-Fas lpr and C57BL/6-Faslpr mice. J Clin Invest 101:696–702
Volpp BD, Nauseef WM, Clark RA (1988) Two cytosolic neutrophil oxidase components absent in autosomal chronic granulomatous disease. Science 242:1295–1297
Zhan S, Vazquez N, Wientjes FB, Budarf ML, Schrock E et al (1996) Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex. Blood 88:2714–2721
Acknowledgments
We thank Michael Schultz, Nadine Lindermann, and Britta Dorn for excellent assistance with the experiments; and Andreas Mayer, Sandra Hoffmann, and members of the ENU core facility for skillful animal care and maintenance of the Ali18 strain. This work was supported in part by grants from the Deutsches Humangenom Projekt (DHGP), the Nationales Genomforschungsnetz (NGFN 01GR0430), and ANABONOS (EU contract No. LSHM-CT-2003-503020) to MHdA, and from the Japan Society for the Promotion of Science (JSPS 19500370) and Nagao Memorial Fund Research to KA. This work was also supported in part by the Study Program of Tokai University Educational System General Research Organization, 2007 Tokai University School of Medicine Research Aid, and Japan Rheumatism Foundation to KA.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Abe, K., Klaften, M., Narita, A. et al. Genome-wide search for genes that modulate inflammatory arthritis caused by Ali18 mutation in mice. Mamm Genome 20, 152–161 (2009). https://doi.org/10.1007/s00335-009-9170-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-009-9170-0