PanR1, a dominant negative missense allele of the gene encoding TNF-alpha (Tnf), does not impair lymphoid development.
A dominant hypomorphic allele of Tnf, PanR1, was identified in a population of G(1) mice born to N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes produced no detectable TNF bioactivity, although normal quantities of immunoreactive TNF were secreted. The phenotype was confined to a critical region on mouse chromosome 17, and then ascribed to a C-->A transversion at position 3480 of the Tnf gene, corresponding to the amino acid substitution P138T. As a result of subunit exchange, the protein exerts a dominant-negative effect on normal TNF trimers, interfering with the trimer/receptor interaction. Homozygotes are highly susceptible to infection by Listeria monocytogenes, confirming the essential role of TNF in innate immune defense. However, PanR1 mutant mice show normal architecture of the spleen and Peyer's patches, suggesting that TNF is not essential for the formation of these lymphoid structures.
Rutschmann
Sophie
S
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
Hoebe
Kasper
K
Zalevsky
Jonathan
J
Du
Xin
X
Mann
Navjiwan
N
Dahiyat
Bassil I
BI
Steed
Paul
P
Beutler
Bruce
B
D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D005038:Ethylnitrosourea / Q000008:administration & dosage; D005260:Female; D005799:Genes, Dominant / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000187:drug effects; D008088:Listeriosis / Q000235:genetics / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense / Q000187:drug effects; D010581:Peyer's Patches / Q000254:growth & development* / Q000276:immunology* / Q000378:metabolism; D011392:Proline / Q000235:genetics; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D012995:Solubility; D013154:Spleen / Q000254:growth & development* / Q000276:immunology* / Q000378:metabolism; D013912:Threonine / Q000235:genetics; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D013912:Threonine; D011392:Proline; D005038:Ethylnitrosourea