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

• Published in: Bone (New York, N.Y.) N.Y.), 2019-04, Vol.121, p.243-254
• Main Authors: Frost, Morten, Tencerova, Michaela, Andreasen, Christina M., Andersen, Thomas L., Ejersted, Charlotte, Svaneby, Dea, Qui, Weimin, Kassem, Moustapha, Zarei, Allahdad, McAlister, William H., Veis, Deborah J., Whyte, Michael P., Frederiksen, Anja L.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Case-Control Studies; Cross-Sectional Studies; Female; Humans; I-kappa B Kinase - genetics; IKBKG; Incontinentia pigmenti; Middle Aged; Mutation; NEMO; NF-κB; Osteopetrosis; Osteopetrosis - genetics; Osteopetrosis - pathology; X-chromosome inactivation; Young Adult
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2019.01.014

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. 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. Seven Caucasian women with IP (age: 24–67 years and BMI: 20.0–35.2 kg/m2) 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