ABCD1 基因突变型等位基因的优先表达在肾上腺脑白质营养不良女性携带者中很常见，但与临床症状无关。
Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms.
机构信息
Department of Medicine, Surgery and Dentistry, Università degli Studi di Milano, Milan, Italy.
出版信息
Orphanet J Rare Dis. 2012 Jan 26;7:10. doi: 10.1186/1750-1172-7-10.
BACKGROUND
Approximately 20% of adrenoleukodystrophy (X-ALD) female carriers may develop clinical manifestations, typically consisting of progressive spastic gait, sensory deficits and bladder dysfunctions. A skewing in X Chromosome Inactivation (XCI), leading to the preferential expression of the X chromosome carrying the mutant ABCD1 allele, has been proposed as a mechanism influencing X-linked adrenoleukodystrophy (X-ALD) carrier phenotype, but reported data so far are conflicting.
METHODS
To shed light into this topic we assessed the XCI pattern in peripheral blood mononuclear cells (PBMCs) of 30 X-ALD carriers. Since a frequent problem with XCI studies is the underestimation of skewing due to an incomplete sample digestion by restriction enzymes, leading to variable results, we developed a pyrosequencing assay to identify samples completely digested, on which to perform the XCI assay. Pyrosequencing was also used to quantify ABCD1 allele-specific expression. Moreover, very long-chain fatty acid (VLCFA) levels were determined in the same patients.
RESULTS
We found severely (≥90:10) or moderately (≥75:25) skewed XCI in 23 out of 30 (77%) X-ALD carriers and proved that preferential XCI is mainly associated with the preferential expression of the mutant ABCD1 allele, irrespective of the manifestation of symptoms. The expression of mutant ABCD1 allele also correlates with plasma VLCFA concentrations.
CONCLUSIONS
Our results indicate that preferential XCI leads to the favored expression of the mutant ABCD1 allele. This emerges as a general phenomenon in X-ALD carriers not related to the presence of symptoms. Our data support the postulated growth advantage of cells with the preferential expression of the mutant ABCD1 allele, but argue against the use of XCI pattern, ABCD1 allele-specific expression pattern and VLCFA plasma concentration as biomarkers to predict the development of symptoms in X-ALD carriers.
背景
大约 20%的肾上腺脑白质营养不良（ALD）女性携带者可能会出现临床表现，通常包括进行性痉挛性步态、感觉缺失和膀胱功能障碍。X 染色体失活（XCI）的偏斜，导致优先表达携带突变 ABCD1 等位基因的 X 染色体，被认为是影响 X 连锁肾上腺脑白质营养不良（X-ALD）携带者表型的一种机制，但迄今为止报告的数据存在冲突。
方法
为了阐明这一主题，我们评估了 30 名 X-ALD 携带者外周血单核细胞（PBMCs）中的 XCI 模式。由于 XCI 研究中经常存在一个问题，即由于限制酶不完全消化导致偏斜低估，从而导致结果不一致，因此我们开发了一种焦磷酸测序测定法来识别完全消化的样本，以便在其上进行 XCI 测定。焦磷酸测序还用于定量 ABCD1 等位基因特异性表达。此外，还在同一患者中测定了非常长链脂肪酸（VLCFA）水平。
结果
我们发现 30 名 X-ALD 携带者中有 23 名（77%）存在严重（≥90:10）或中度（≥75:25）偏斜的 XCI，并证明优先 XCI 主要与突变 ABCD1 等位基因的优先表达相关，与症状的表现无关。突变 ABCD1 等位基因的表达也与血浆 VLCFA 浓度相关。
结论
我们的结果表明，优先 XCI 导致突变 ABCD1 等位基因的优先表达。这是 X-ALD 携带者中一种与症状无关的普遍现象。我们的数据支持优先表达突变 ABCD1 等位基因的细胞具有生长优势的假设，但反对将 XCI 模式、ABCD1 等位基因特异性表达模式和 VLCFA 血浆浓度用作预测 X-ALD 携带者症状发展的生物标志物。
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