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Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3046-51. doi: 10.1073/pnas.0915098107. Epub 2010 Jan 28.

A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha.

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Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.


Null alleles of the gene encoding NEMO (NF-kappaB 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 IkappaB 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-kappaB p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond IkappaB alpha degradation, and offers a biochemical explanation for rare immune deficiencies in man.

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