Absence of an osteopetrosis phenotype in IKBKG (NEMO) mutation-positive women: A case-control study.
Bone. 2019 Jan 16;:
Authors: Frost M, Tencerova M, Andreasen CM, Andersen TL, Ejersted C, Svaneby D, Qui W, Kassem M, Zarei A, McAlister WH, Veis DJ, Whyte MP, Frederiksen AL
BACKGROUND: NF-?B 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-?B). Animal studies suggest NEMO is required for NF-?B 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; ?-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-?B activity was quantitated in BM-MSCs using a luciferase NF-?B reporter assay.
RESULTS: 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-?B activity was lower in BM-MSCs from IKBKG mutation carriers (n?=?5) compared to controls (3094?±?679 vs. 5422?±?1038/?g protein, p?0.01). However, no differences were identified on skeletal radiographics, aBMD, ?-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.
PMID: 30659980 [PubMed – as supplied by publisher]