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基于全面重测序和与 ALD 表型的关联研究,鉴定 X 连锁肾上腺脑白质营养不良 (ALD) 患者 ABCD1、ABCD2、ABCD3 和 ABCD4 基因的新型 SNPs。

Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes.

机构信息

Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.

出版信息

Neurogenetics. 2011 Feb;12(1):41-50. doi: 10.1007/s10048-010-0253-6. Epub 2010 Jul 27.


DOI:10.1007/s10048-010-0253-6
PMID:20661612
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3029816/
Abstract

Adrenoleukodystrophy (ALD) is an X-linked disorder affecting primarily the white matter of the central nervous system occasionally accompanied by adrenal insufficiency. Despite the discovery of the causative gene, ABCD1, no clear genotype-phenotype correlations have been established. Association studies based on single nucleotide polymorphisms (SNPs) identified by comprehensive resequencing of genes related to ABCD1 may reveal genes modifying ALD phenotypes. We analyzed 40 Japanese patients with ALD. ABCD1 and ABCD2 were analyzed using a newly developed microarray-based resequencing system. ABCD3 and ABCD4 were analyzed by direct nucleotide sequence analysis. Replication studies were conducted on an independent French ALD cohort with extreme phenotypes. All the mutations of ABCD1 were identified, and there was no correlation between the genotypes and phenotypes of ALD. SNPs identified by the comprehensive resequencing of ABCD2, ABCD3, and ABCD4 were used for association studies. There were no significant associations between these SNPs and ALD phenotypes, except for the five SNPs of ABCD4, which are in complete disequilibrium in the Japanese population. These five SNPs were significantly less frequently represented in patients with adrenomyeloneuropathy (AMN) than in controls in the Japanese population (p=0.0468), whereas there were no significant differences in patients with childhood cerebral ALD (CCALD). The replication study employing these five SNPs on an independent French ALD cohort, however, showed no significant associations with CCALD or pure AMN. This study showed that ABCD2, ABCD3, and ABCD4 are less likely the disease-modifying genes, necessitating further studies to identify genes modifying ALD phenotypes.

摘要

肾上腺脑白质营养不良(ALD)是一种 X 连锁疾病,主要影响中枢神经系统的白质,偶尔伴有肾上腺功能不全。尽管已经发现了致病基因 ABCD1,但尚未建立明确的基因型-表型相关性。基于 ABCD1 相关基因的全面重测序确定的单核苷酸多态性(SNP)的关联研究可能会揭示修饰 ALD 表型的基因。我们分析了 40 名日本 ALD 患者。使用新开发的基于微阵列的重测序系统分析 ABCD1 和 ABCD2。直接核苷酸序列分析用于分析 ABCD3 和 ABCD4。对具有极端表型的独立法国 ALD 队列进行了复制研究。确定了 ABCD1 的所有突变,并且基因型与 ALD 表型之间没有相关性。对 ABCD2、ABCD3 和 ABCD4 的全面重测序确定的 SNP 进行了关联研究。除了完全处于不平衡状态的 ABCD4 的五个 SNP 外,这些 SNP 与 ALD 表型之间没有显著关联。在日本人群中,患有肾上腺脑脊髓神经病(AMN)的患者中这些 ABCD4 的五个 SNP 的代表性明显低于对照组(p=0.0468),而在患有儿童脑性 ALD(CCALD)的患者中没有显着差异。然而,在对独立的法国 ALD 队列进行这些五个 SNP 的复制研究时,与 CCALD 或纯 AMN 均无显著关联。这项研究表明,ABCD2、ABCD3 和 ABCD4 不太可能是疾病修饰基因,需要进一步研究以确定修饰 ALD 表型的基因。

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[3]
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[4]
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[5]
A novel ABCD1 gene mutation causes adrenomyeloneuropathy presenting with spastic paraplegia: A case report.

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[6]
Adrenomyeloneuropathy with Later Development of Cerebral Form Caused by a Hemizygous Splice-site Variant in ABCD1.

Intern Med. 2024-4-1

[7]
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J Neurosci Res. 2021-12

[8]
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[9]
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[10]
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本文引用的文献

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Biochem Biophys Res Commun. 2008-12-5

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