The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis.
The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis.
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DOI：
10.1186/scrt130
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发表时间：
2012-10-04
影响因子：
7.5
通讯作者：
Hacia JG
中科院分区：
文献类型：
--
作者：
Wang XM;Yik WY;Zhang P;Lu W;Dranchak PK;Shibata D;Steinberg SJ;Hacia JG
x -连锁肾上腺脑白质营养不良（X-ALD）是一种具有可变表达性的复杂疾病，影响神经系统、肾上腺皮质系统和男性生殖系统。虽然已知ABCD1突变为X-ALD提供了遗传基础，但其发病机制尚未完全阐明。虽然血液中超长链脂肪酸（VLCFA）水平升高和培养成纤维细胞中VLCFA分解代谢活性降低是用于识别ABCD1突变携带者的生物标志物，但过氧化物酶体脂质代谢在疾病病因学中的作用尚不清楚。用表达OCT4、SOX2、KLF4和c-MYC因子的逆转录病毒载体转导两名由ABCD1移码或错义突变引起的儿童脑型疾病（CCALD）的男性患者和三名健康供者的原代皮肤成纤维细胞。对候选诱导多能干细胞（iPSCs）进行全局基因表达、DNA甲基化、DNA拷贝数变异和基因分型分析，并通过体外分化和畸胎瘤形成测试其多能性。通过质谱法测定健康供体和CCALD患者原代成纤维细胞和iPSCs中饱和VLCFA （sVLCFA）和浆磷脂原水平。来自CCALD患者和健康供体的皮肤成纤维细胞被重新编程为经过验证的iPSCs。与成纤维细胞不同，CCALD患者iPSCs显示与过氧化物酶体丰度和神经炎症相关的差异表达基因（DEGs）。此外，与成纤维细胞相比，来自患者的iPSCs的sVLCFA水平与来自对照组的iPSCs相比没有显着差异。在所有细胞类型中，检测的浆磷脂水平与ABCD1突变状态无关。正常的ABCD1基因功能不需要将皮肤成纤维细胞重编程为iPSCs或维持多能性。相对于在成纤维细胞中发现的deg，在CCALD患者和对照iPSCs的比较中发现的deg更符合关于疾病发病机制的主要假设。这些deg与sVLCFA水平的差异无关，后者不随ABCD1突变状态而变化。突出显示的基因为在动物模型和人体组织标本中探索致病机制提供了新的线索。我们建议这些iPSC资源的应用将包括协助鉴定遗传和环境修饰剂以及针对受影响细胞群和患者基因型量身定制的治疗干预筛选。
X-linked adrenoleukodystrophy (X-ALD) is a complex disorder with variable expressivity that affects the nervous, adrenocortical and male reproductive systems. Although ABCD1 mutations are known to provide the genetic basis for X-ALD, its pathogenesis is not fully elucidated. While elevated very long chain fatty acid (VLCFA) levels in blood and reduced VLCFA catabolic activity in cultured fibroblasts are biomarkers used to identify ABCD1 mutation carriers, the roles peroxisomal lipid metabolism play in disease etiology are unknown. Primary skin fibroblasts from two male patients with the childhood cerebral form of the disease (CCALD) caused by ABCD1 frameshift or missense mutations and three healthy donors were transduced with retroviral vectors expressing the OCT4, SOX2, KLF4 and c-MYC factors. Candidate induced pluripotent stem cells (iPSCs) were subject to global gene expression, DNA methylation, DNA copy number variation, and genotyping analysis and tested for pluripotency through in vitro differentiation and teratoma formation. Saturated VLCFA (sVLCFA) and plasmalogen levels in primary fibroblasts and iPSCs from healthy donors as well as CCALD patients were determined through mass spectroscopy. Skin fibroblasts from CCALD patients and healthy donors were reprogrammed into validated iPSCs. Unlike fibroblasts, CCALD patient iPSCs show differentially expressed genes (DEGs) relevant to both peroxisome abundance and neuroinflammation. Also, in contrast to fibroblasts, iPSCs from patients showed no significant difference in sVLCFA levels relative to those from controls. In all cell types, the plasmalogen levels tested did not correlate with ABCD1 mutation status. Normal ABCD1 gene function is not required for reprogramming skin fibroblasts into iPSCs or maintaining pluripotency. Relative to DEGs found in fibroblasts, DEGs uncovered in comparisons of CCALD patient and control iPSCs are more consistent with major hypotheses regarding disease pathogenesis. These DEGs were independent of differences in sVLCFA levels, which did not vary according to ABCD1 mutation status. The highlighted genes provide new leads for pathogenic mechanisms that can be explored in animal models and human tissue specimens. We suggest that these iPSC resources will have applications that include assisting efforts to identify genetic and environmental modifiers and screening for therapeutic interventions tailored towards affected cell populations and patient genotypes.
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DOI：
10.1158/1940-6207.capr-10-0387
发表时间：
2011-07
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Chen HY;White E
通讯作者：
White E
影响因子：
3.5
作者：
Asheuer, M;Bieche, I;Aubourg, P
通讯作者：
Aubourg, P
影响因子：
4.4
作者：
Arora, K;Gwinn, WM;Constant, SL
通讯作者：
Constant, SL
影响因子：
3.8
作者：
Hubbard, Walter C.;Moser, Ann B.;Raymond, Gerald V.
通讯作者：
Raymond, Gerald V.
影响因子：
4.8
作者：
Isenberg, Jeff S.;Jia, Yifeng;Roberts, David D.
通讯作者：
Roberts, David D.