Decreased Expression in Nuclear Factor-κB Essential Modulator Due to a Novel Splice-Site Mutation Causes X-linked Ectodermal Dysplasia with Immunodeficiency
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X-linked ectodermal dysplasia with immunodeficiency (XL-ED-ID) is caused by hypomorphic mutations in NEMO, which encodes nuclear factor-kappaB (NF-κB) essential modulator. We identified a novel mutation, 769−1 G>C, at the splicing acceptor site of exon 7 in NEMO in a Japanese patient with XL-ED-ID. Although various abnormally spliced NEMO messenger RNAs (mRNAs) were observed, a small amount of wild-type (WT) mRNA was also identified. Decreased NEMO protein expression was detected in various lineages of leukocytes. Although one abnormally spliced NEMO protein showed residual NF-κB transcription activity, it did not seem to exert a dominant-negative effect against WT-NEMO activity. CD4+ T cell proliferation was impaired in response to measles and mumps, but not rubella. These results were consistent with the clinical and laboratory findings of the patient, suggesting the functional importance of NEMO against specific viral infections. The 769−1 G>C mutation is responsible for decreased WT-NEMO protein expression, resulting in the development of XL-ED-ID.
KeywordsNEMO XL-ED-ID IKBKG splice-site mutation measles
This work was supported by a Grant-in-Aid for Young Scientist (B) No. 20790731 from Japan Society for the Promotion of Science. This work was also supported by the grants from the Japanese Ministry of Education, Culture, Sports, and Technology and grants from the Japanese Ministry of Health, Labor, and Welfare. We wish to thank the Analysis Center of Life Science, Hiroshima University for the use of their facilities. We also thank Natsuki Nabe and Yuki Takaoka for their valuable help with the reporter assay.
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