Journal of Clinical Immunology

, Volume 31, Issue 5, pp 762–772 | Cite as

Decreased Expression in Nuclear Factor-κB Essential Modulator Due to a Novel Splice-Site Mutation Causes X-linked Ectodermal Dysplasia with Immunodeficiency

  • Shuhei Karakawa
  • Satoshi OkadaEmail author
  • Miyuki Tsumura
  • Yoko Mizoguchi
  • Norioki Ohno
  • Shin’ichiro Yasunaga
  • Motoaki Ohtsubo
  • Tomoki Kawai
  • Ryuta Nishikomori
  • Takemasa Sakaguchi
  • Yoshihiro Takihara
  • Masao Kobayashi


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.


NEMO 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.

Supplementary material

10875_2011_9560_Fig6_ESM.jpg (30 kb)
Supplementary Figure

WT and mutant NEMO plasmids (+171-NEMO and +64-NEMO) were transfected into NEMO null cells and subjected to an immunoblot analysis. The WT-NEMO and +171-NEMO were detected at approximately 50 and 57 kDa, respectively. The +64-NEMO protein was not detected by either the anti-NEMO or anti-Flag antibodies (JPEG 30 kb)

10875_2011_9560_MOESM1_ESM.tif (228 kb)
High resolution image (TIFF 228 kb)
10875_2011_9560_MOESM2_ESM.docx (1.5 mb)
Supplementary Table Primers information (DOCX 1572 kb)


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Shuhei Karakawa
    • 1
  • Satoshi Okada
    • 1
    Email author
  • Miyuki Tsumura
    • 1
  • Yoko Mizoguchi
    • 1
  • Norioki Ohno
    • 1
  • Shin’ichiro Yasunaga
    • 2
  • Motoaki Ohtsubo
    • 2
  • Tomoki Kawai
    • 3
  • Ryuta Nishikomori
    • 3
  • Takemasa Sakaguchi
    • 4
  • Yoshihiro Takihara
    • 2
  • Masao Kobayashi
    • 1
  1. 1.Department of PediatricsHiroshima University Graduate School of Biomedical SciencesHiroshimaJapan
  2. 2.Department of Stem Cell Biology, Research Institute for Radiation Biology and MedicineHiroshima UniversityHiroshimaJapan
  3. 3.Department of PediatricsKyoto University Graduate School of MedicineKyotoJapan
  4. 4.Department of VirologyHiroshima University Graduate School of Biomedical SciencesHiroshimaJapan

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