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*

*Kontaktforfatter

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

4 Citationer (Scopus)

Abstract

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.

OriginalsprogEngelsk
TidsskriftBone
Vol/bind121
Sider (fra-til)243-254
Antal sider12
ISSN8756-3282
DOI
StatusUdgivet - apr. 2019
Udgivet eksterntJa

Bibliografisk note

Funding Information:
The study was supported by A.P. Moeller and Chastine Mc-Kinney Moeller Foundation for General Purposes, Region of Southern Denmark, Odense University Research Foundation, Aase og Ejnar Danielsens Fond, Novo Nordisk Foundation (NNF15OC0016284), and Shriners Hospitals for Children. MT was supported by a postdoctoral fellowship grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation. DJV and AZ were supported by NIH (AR070030).

Funding Information:
The study was supported by A.P. Moeller and Chastine Mc-Kinney Moeller Foundation for General Purposes , Region of Southern Denmark , Odense University Research Foundation , Aase og Ejnar Danielsens Fond , Novo Nordisk Foundation ( NNF15OC0016284 ), and Shriners Hospitals for Children . MT was supported by a postdoctoral fellowship grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation. DJV and AZ were supported by NIH ( AR070030 ).

Publisher Copyright:
© 2019 Elsevier Inc.

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