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


ABSTRACT: 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?

SUBMITTER: Frost M 

PROVIDER: S-EPMC6457251 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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