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PNAS 107 (7): 3046-3051

Copyright © 2010 by the National Academy of Sciences.


A mutation of Ikbkg causes immune deficiency without impairing degradation of I{kappa}B{alpha}

Owen M. Siggsa, Michael Bergera, Philippe Krebsa, Carrie N. Arnolda, Celine Eidenschenka, Christoph Huberb, Elaine Piriea, Nora G. Smarta, Kevin Khovanantha, Yu Xiaa, Gerald McInerneyc, Gunilla B. Karlsson Hedestamc, David Nemazeeb, and Bruce Beutlera,1

Departments of aGenetics and bImmunology, The Scripps Research Institute, La Jolla, CA 92037; and cDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Contributed by Bruce Beutler, December 30, 2009 (sent for review December 17, 2009)

Abstract: Null alleles of the gene encoding NEMO (NF-{kappa}B essential modulator) are lethal in hemizygous mice and men, whereas hypomorphic alleles typically cause a syndrome of immune deficiency and ectodermal dysplasia. Here we describe an allele of Ikbkg in mice that impaired Toll-like receptor signaling, lymph node formation, development of memory and regulatory T cells, and Ig production, but did not cause ectodermal dysplasia. Degradation of I{kappa}B{alpha}, which is considered a primary requirement for NEMO-mediated immune signaling, occurred normally in response to Toll-like receptor stimulation, yet ERK phosphorylation and NF-{kappa}B p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond I{kappa}B{alpha} degradation, and offers a biochemical explanation for rare immune deficiencies in man.

Key Words: mutagenesis • N-ethyl-nitrosourea • nuclear factor–{kappa}B essential modulator • p65 • Toll-like receptor

Author contributions: O.M.S. and B.B. designed research; O.M.S., M.B., P.K., C.A., C.E., C.H., E.P., K.K., and Y.X. performed research; G.M., G.B.K.H., and D.N. contributed new reagents/analytic tools; O.M.S. and B.B. analyzed data; and O.M.S., N.G.S., and B.B. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: bruce{at}

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