Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy
Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy
复制标题
DOI：
10.1093/hmg/ddi140
复制
发表时间：
2005-05-15
影响因子：
3.5
通讯作者：
Aubourg, P
中科院分区：
文献类型：
--
作者：
Asheuer, M;Bieche, I;Aubourg, P
儿童肾上腺脑白质营养不良（CCER）、肾上腺脊髓神经病（AMN）和AMN伴脑脱髓鞘（AMN-C）是X连锁肾上腺脑白质营养不良（ALD）的主要表型变异。它是由ABCD 1基因突变引起的，ABCD 1基因编码一半大小的过氧化物酶体转运蛋白，必须二聚化才能发挥功能。ALD的生化标志是血浆和组织中极长链脂肪酸（VLCFA）的积累。然而，ALD表型与ABCD 1基因突变或ALD患者血浆和成纤维细胞中VLCFA的积累之间没有相关性。基因型-表型相关性的缺乏表明修饰基因的存在。为了阐明ALD表型变异的机制，我们研究了ABCD 1、同一家族的其他三个过氧化物酶体转运蛋白基因（ABCD 2、ABCD 3和ABCD 4）和参与VLCFA代谢的两个VLCFA合成酶基因（VLCS和BG 1）的表达，以及具有CCER、AMN-C和AMN表型的ALD患者的正常白色物质（WM）中的VLCFA浓度。这项研究表明：（1）ABCD 1基因突变导致ALD蛋白截短，不太可能导致ALD表型变异;（2）正常WM中饱和VLCFA的积累与ALD表型相关;（3）ABCD 4和BG 1的表达，而不是ABCD 2、ABCD 3和VLCS基因的表达，往往与疾病的严重程度相关，在ALD发病机制的早期起作用。
Childhood cerebral adrenoleukodystrophy (CCER), adrenomyeloneuropathy (AMN) and AMN with cerebral demyelination (AMN-C) are the main phenotypic variants of X-linked adrenoleukodystrophy (ALD). It is caused by mutations in the ABCD1 gene encoding a half-size peroxisomal transporter that has to dimerize to become functional. The biochemical hallmark of ALD is the accumulation of very-long-chain fatty acids (VLCFA) in plasma and tissues. However, there is no correlation between the ALD phenotype and the ABCD1 gene mutations or the accumulation of VLCFA in plasma and fibroblast from ALD patients. The absence of genotype- phenotype correlation suggests the existence of modifier genes. To elucidate the mechanisms underlying the phenotypic variability of ALD, we studied the expression of ABCD1, three other peroxisomal transporter genes of the same family (ABCD2, ABCD3 and ABCD4) and two VLCFA synthetase genes (VLCS and BG1) involved in VLCFA metabolism, as well as the VLCFA concentrations in the normal white matter (WM) from ALD patients with CCER, AMN-C and AMN phenotypes. This study shows that: (1) ABCD1 gene mutations leading to truncated ALD protein are unlikely to cause variation in the ALD phenotype; (2) accumulation of saturated VLCFA in normal-appearing WM correlates with ALD phenotype and (3) expression of the ABCD4 and BG1, but not of the ABCD2, ABCD3 and VLCS genes, tends to be correlated with the severity of the disease, acting early in the pathogenesis of ALD.