Absence of an osteopetrosis phenotype in IKBKG (NEMO) mutation-positive women: A case-control study

Morten Frost, Michaela Tencerova, Christina M. Andreasen, Thomas L. Andersen, Charlotte Ejersted, Dea Svaneby, Weimin Qui, Moustapha Kassem, Allahdad Zarei, William H. McAlister, Deborah J. Veis, Michael P. Whyte, Anja L. Frederiksen

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4 Scopus citations


Background: NF-κB essential modulator (NEMO), encoded by IKBKG, is necessary for activation of the ubiquitous transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Animal studies suggest NEMO is required for NF-κB mediated bone homeostasis, but this has not been thoroughly studied in humans. IKBKG loss-of-function mutation causes incontinentia pigmenti (IP), a rare X-linked disease featuring linear hypopigmentation, alopecia, hypodontia, and immunodeficiency. Single case reports describe osteopetrosis (OPT) in boys carrying hypomorphic IKBKG mutations. Method: We studied the bone phenotype in women with IP with evaluation of radiographs of the spine and non-dominant arm and leg; lumbar spine and femoral neck aBMD using DXA; μ-CT and histomorphometry of trans-iliac crest biopsy specimens; bone turnover markers; and cellular phenotype in bone marrow skeletal (stromal) stem cells (BM-MSCs) in a cross-sectional, age-, sex-, and BMI-matched case-control study. X-chromosome inactivation was measured in blood leucocytes and BM-MSCs using a PCR method with methylation of HpaII sites. NF-κB activity was quantitated in BM-MSCs using a luciferase NF-κB reporter assay. Results: Seven Caucasian women with IP (age: 24–67 years and BMI: 20.0–35.2 kg/m 2 ) and IKBKG mutation (del exon 4–10 (n = 4); c.460C>T (n = 3)) were compared to matched controls. The IKBKG mutation carriers had extremely skewed X-inactivation (>90:10%) in blood, but not in BM-MSCs. NF-κB activity was lower in BM-MSCs from IKBKG mutation carriers (n = 5) compared to controls (3094 ± 679 vs. 5422 ± 1038/μg protein, p < 0.01). However, no differences were identified on skeletal radiographics, aBMD, μ-architecture of the iliac crest, or bone turnover markers. The IKBKG mutation carriers had a 1.7–fold greater extent of eroded surfaces relative to osteoid surfaces (p < 0.01), and a 2.0–fold greater proportion of arrested reversal surface relative to active reversal surface (p < 0.01). Conclusion: Unlike mutation-positive males, the IKBKG mutation-positive women did not manifest OPT.

Original languageEnglish
Pages (from-to)243-254
Number of pages12
StatePublished - Apr 2019


  • Incontinentia pigmenti
  • NEMO
  • NF-κB
  • Osteopetrosis
  • X-chromosome inactivation


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