Absence of an osteopetrosis phenotype in IKBKG (NEMO) mutation-positive women: A case- control study
Absence of an osteopetrosis phenotype in IKBKG (NEMO) mutation-positive women: A case- control study
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DOI：
10.1016/j.bone.2019.01.014
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发表时间：
2019-04-01
期刊：
影响因子：
4.1
通讯作者：
Frederiksen, Anja L.
中科院分区：
文献类型：
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作者：
Frost, Morten;Tencerova, Michaela;Frederiksen, Anja L.
背景：由IKBKG编码的核因子-kappaB必需调节剂(Nemo)是激活核因子kappa轻链增强子活化B细胞所必需的。动物研究表明，NEMO是核因子-kappaB介导的骨稳态所必需的，但这在人类身上还没有得到彻底的研究。IKBKG功能缺失突变导致色素性失禁(IP)，这是一种罕见的X连锁疾病，以线性色素减退、脱发、牙齿减少和免疫缺陷为特征。单个病例报告描述了携带低构型IKBKG突变的男孩的骨化症(OPT)。方法：在一项横断面、年龄、性别和BMI匹配的病例对照研究中，我们研究了IP妇女的骨表型，包括脊柱和非优势臂和腿的X线片；腰椎和股骨颈的DXA骨密度；经髂骨顶活检标本的MU-CT和组织形态计量学；骨转换标志物；以及骨髓基质干细胞(BM-MSCs)的细胞表型。用聚合酶链式反应方法检测外周血白细胞和骨髓间充质干细胞中X染色体的失活情况。结果：7名高加索女性，年龄24~67岁，体重指数20.0~35.2 kg/m(2)，有IKBKG突变(del外显子4~10(n=4)；c.460C>；T(n=3))。IKBKG突变携带者在血液中有极不对称的X-失活(>；90：10%)，但在BM-MSCs中没有。来自IKBKG突变携带者(n=5)的BM-MSCs的核因子-kappaB活性低于对照组(3094+/-679比5422+/-1038/mU蛋白，p<；0.01)。然而，在骨骼X线片、aBMD、髂骨骨结构或骨转换标志物方面没有发现差异。与类骨质表面相比，IKBKG突变携带者的侵蚀表面范围增加了1.7倍(p<；0.01)，反转面受阻的比例是活跃反转面的2.0倍(p<；0.01)。结论：与突变阳性男性不同，IKBKG突变阳性女性没有表现出OPT。
Background: NF-kappa 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-kappa B). Animal studies suggest NEMO is required for NF-kappa 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; mu-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-kappa B activity was quantitated in BM-MSCs using a luciferase NF-kappa B 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-kappa B activity was lower in BM-MSCs from IKBKG mutation carriers (n = 5) compared to controls (3094 +/- 679 vs. 5422 +/- 1038/mu g protein, p < 0.01). However, no differences were identified on skeletal radiographics, aBMD, mu-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.