X染色体非随机失活在肾上腺-脑白质营养不良女性杂合子发病中的作用

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disease caused by mutations in the ABCD1 gene. It has been demonstrated that X-ALD not only affects males, but also female carriers. While it is often stated that in recessive X-linked disorders heterozygotes are asymptomatic, it is known that for some X-linked disorders the dichotomy between recessive and dominant does not apply and there are conditions where heterozygosity may represent a disease state. In some cases, this has shown to be due to unfavorable skewing of X chromosome inactivation (XCI), where the X chromosome carrying a mutant allele is the predominantly active X. However, for X-ALD, the cause of the manifestations in heterozygous females has not been determined definitively, and a direct association between the clinical phenotype and the X inactivation phenotype is not found consistently. To investigate the mechanism influencing X-ALD carrier phenotype, symptomatic and asymptomatic carriers, unaffected female members of X-ALD pedigrees and unrelated control females will be studied in the project. ABCD1 genotype, transcript analysis, XCI pattern, karyotype, XIST genotype, and microsatellite analyses will be utilized. Our objective is to establish a comprehensive assessment of heterozygous females, and confirm that skewed XCI in favor of the mutant allele would be the pathogenesis of X-ALD in manifesting carriers, and determine whether skewing is more consistent with genetically influenced or completely random XCI.

肾上腺-脑白质营养不良（ALD）过去被列为X-连锁隐性遗传病，但ALD症状性杂合子的存在，对传统的X-连锁隐性遗传病的遗传法则提出了挑战。目前，ALD女性杂合子的发病机制尚不清楚。为探讨ALD女性杂合子的不同临床表型是否由X染色体失活方式不同而影响致病基因表达所致，本项目首先对ALD家系中的女性成员进行ABCD1基因突变筛查；对其中的杂合子进一步分析其野生型/突变型等位基因表达比例；再利用人类雄激素受体（AR）基因多态性检测她们的X染色体失活模式；对X染色体非随机失活的女性进一步查找导致非随机失活的可能原因。本项目旨在建立一套较全面的女性杂合子分析方法，首次证实X染色体非随机失活使野生型ABCD1基因表达下降是导致ALD女性杂合子发病的原因，从而为ALD及其他X-连锁遗传病女性发病机制的研究提供实验依据。

肾上腺-脑白质营养不良（ALD）过去被列为X-连锁隐性遗传病，但ALD症状性杂合子的存在，对传统的X-连锁隐性遗传病的遗传法则提出了挑战。目前，ALD女性杂合子的发病机制尚不清楚。为探讨ALD女性杂合子的不同临床表型是否由X染色体失活方式不同而影响致病基因表达所致，本项目首先对ALD家系中的女性成员进行ABCD1基因突变筛查；对其中的杂合子进一步分析其野生型/突变型等位基因表达比例；再利用人类雄激素受体（AR）基因多态性检测她们的X染色体失活模式；对X染色体非随机失活的女性进一步查找导致非随机失活的可能原因。本项目建立了从DNA途径、RNA途径基因突变分析，野生型/突变型等位基因表达比例分析到X染色体失活模式检测的女性杂合子较全面的分析方法，并初步证实X染色体非随机失活使野生型ABCD1基因表达下降可能是导致X-ALD女性杂合子发病的原因，从而为ALD及其他X-连锁遗传病女性发病机制的研究提供了实验依据。