Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy
Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy
复制标题
SMN2甲基化与中国脊髓性肌萎缩症儿童疾病严重程度的关系
DOI：
10.1631/jzus.b1500072
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发表时间：
2016-01-01
影响因子：
5.1
通讯作者：
Song, Fang
中科院分区：
文献类型：
--
作者：
Cao, Yan-yan;Qu, Yu-jin;Song, Fang
The homozygous loss of the survival motor neuron 1 (SMN1) gene is the primary cause of spinal muscular atrophy (SMA), a neuromuscular degenerative disease. A genetically similar gene, SMN2, which is not functionally equivalent in all SMA patients, modifies the clinical SMA phenotypes. We analyzed the methylation levels of 4 CpG islands (CGIs) in SMN2 in 35 Chinese children with SMA by MassARRAY. We found that three CpG units located in CGI 1 (nucleotides (nt) −871, −735) and CGI 4 (nt +999) are significantly hypomethylated in SMA type III compared with type I or II children after receiving Bonferroni correction. In addition to the differentially methylated CpG unit of nt −871, the methylation level of the nt −290/−288/−285 unit was negatively correlated with the expression of SMN2 full-length transcripts (SMN2-fl). In addition, the methylation level at nt +938 was inversely proportional to the ratio of SMN2-fl and lacking exon 7 transcripts (SMN2-Δ7, fl/Δ7), and was not associated with the SMN2 transcript levels. Thus, we can conclude that SMN2 methylation may regulate the SMA disease phenotype by modulating its transcription.中文概要目 的分析我国脊肌萎缩症(SMA)患儿SMN2 基因甲基化水平与其转录水平,并初步探讨该基因的甲基化修饰是否影响我国儿童型SMA 疾病的严重程度。创新点首次在中国儿童型SMA 人群中分析SMN2 基因甲基化状态,提示该基因的甲基化模式在不同人种间具有一定保守性,而甲基化单元的甲基化状态可能具有种族差异。本研究也初步提示SMN2基因甲基化水平除了可能影响该基因的转录,还可能影响基因的可变剪接。方 法应用MassARRAY 的方法检测35 例SMA 患儿(SMN1 基因纯合缺失,SMN2 基因3 拷贝)外周血细胞中SMN2 基因甲基化状态;应用实时聚合酶链反应(real-time PCR)的方法检测SMN2基因不同转录本的表达水平;分析SMN2 基因甲基化与该基因的转录以及SMA 疾病严重程度的关系。结 论位于甲基化岛1 的两个甲基化单元(nt −871 和 nt −735)和位于甲基化岛4 的nt +999 甲基化单元的甲基化水平在III 型患儿中显著低于II 型和I 型患儿;nt −871 和nt −290/−288/−285 甲基化单元的甲基化水平与SMN2 基因全长转录本(SMN2-fl)的转录水平呈负相关。此外, nt +938甲基化单元的甲基化水平与SMN2 基因全长转录本与跳跃外显子7 转录本的比值(fl/Δ7)呈负相关,但与SMN2 的转录水平无关。因此,我们初步得出SMN2 基因甲基化可能通过调控其转录而影响我国儿童型SMA 的疾病表型。