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CLC number: R746.4

On-line Access: 2016-01-06

Received: 2015-03-24

Revision Accepted: 2015-11-07

Crosschecked: 2015-12-16

Cited: 1

Clicked: 1640

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Fang Song

http://orcid.org/0000-0002-8844-1331

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Journal of Zhejiang University SCIENCE B 2016 Vol.17 No.1 P.76-82

10.1631/jzus.B1500072


Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy


Author(s):  Yan-yan Cao, Yu-jin Qu, Sheng-xi He, Yan Li, Jin-li Bai, Yu-wei Jin, Hong Wang, Fang Song

Affiliation(s):  Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, China

Corresponding email(s):   yanyancao2@163.com, songf_558@263.net

Key Words:  CpG island, Methylation, Survival motor neuron 2 (SMN2), Spinal muscular atrophy


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Yan-yan Cao, Yu-jin Qu, Sheng-xi He, Yan Li, Jin-li Bai, Yu-wei Jin, Hong Wang, Fang Song. Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy[J]. Journal of Zhejiang University Science B, 2016, 17(1): 76-82.

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journal="Journal of Zhejiang University Science B",
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pages="76-82",
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publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1500072"
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Abstract: 
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-(7, fl/(7), 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.

SMN2基因甲基化与中国儿童型脊肌萎缩症疾病严重程度的相关分析

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(SMN2fl)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。

关键词:CpG岛;甲基化;运动神经元存活基因2;脊肌萎缩症

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Reference

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[16]List of electronic supplementary materials

[17]Table S1 Primers for SMN2 CGIs cloning sequencing

[18]Table S2 Primers for SMN2 CGIs nested PCR

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