脊髓性肌萎缩症患儿SMN1和SMN2基因拷贝数与临床表型的相关性分析
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摘要
目的对脊髓性肌萎缩症(SMA)患儿的运动神经元存活基因1(SMN1)和SMN2拷贝数与临床表型之间的关系进行分析,提高对SMA患儿的早期诊断和临床干预水平。方法选取45例SMA患儿,应用多重连接依赖性探针扩增技术对SMN1和SMN2基因拷贝数进行检测,分析SMN基因拷贝数同临床表型之间的关系。结果 45例SMA患儿中,SMN1第7和8外显子纯合缺失者为42例,占93%(42/45);仅有第7外显子缺失者为3例,占7%(3/45)。SMA不同临床分型和SMN1基因第7、8外显子缺失类型间无相关性(P>0.05);SMA患儿和健康儿童的SMN2基因拷贝数分布差异有统计学意义(P<0.05),前者以2和3拷贝者居多,后者以1和2拷贝者居多;不同SMA临床分型间SMN2拷贝数分布差异有统计学意义(P<0.05),SMN2基因为2拷贝者发病年龄明显小于3和4拷贝者。Ⅰ型SMA患儿中SMN2拷贝数以2或3拷贝者居多,Ⅱ型以3拷贝者居多,Ⅲ型以3或4拷贝者居多。随着SMN2拷贝数增加,患儿发病年龄越大,保有的运动功能和临床结局越好,SMN2基因拷贝数同临床结局间的关系存在显著性差异(P<0.05)。结论 SMN2基因通过剂量补偿效应减轻SMA疾病严重程度,SMN2拷贝数同SMA临床表型具有相关性,可将其作为预测疾病严重程度的依据之一。
Objective To study the association of copy number of SMN1 and SMN2 with clinical phenotypes in children with spinal muscular atrophy(SMA). Methods A total of 45 children with SMA were enrolled. Multiplex ligation-dependent probe amplification was used to measure the gene copy numbers of SMN1 and SMN2. The association of copy number of SMN1 and SMN2 with clinical phenotypes was analyzed. Results Of the 45 children with SMA,42(93%) had a homozygous deletion of SMN1 exons 7 and 8, and 3(7%) had a deletion of SMN1 exon 7 alone. No association was found between SMA clinical types and the deletion types of SMN1 exons 7 and 8(P>0.05). There was a significant difference in the distribution of SMN2 gene copy numbers between the children with SMA and the healthy children(P<0.05). The children with SMA usually had two or three copies of SMN2 gene, while the healthy children usually had one or two copies of SMN2 gene. There was a significant difference in the distribution of SMN2 copy numbers among the children with different SMA clinical types(P <0.05). The children with two copies of SMN2 gene had a significantly lower age of onset than those with three or four copies. Most of the children with type I SMA had two or three copies of SMN2 gene. Most of the children with type II SMA had three copies of SMN2 gene. Most of the children with type III SMA had three or four copies of SMN2 gene. Children with a higher copy number of SMN2 gene tended to have an older age of onset and better motor function and clinical outcome, and there was a significant association between SMN2 gene copy number and clinical outcome(P<0.05). Conclusions The SMN2 gene can reduce the severity of SMA via the dosage compensation effect. SMN2 copy number is associated with the phenotype of SMA, and therefore, it can be used to predict disease severity.
Objective To study the association of copy number of SMN1 and SMN2 with clinical phenotypes in children with spinal muscular atrophy(SMA). Methods A total of 45 children with SMA were enrolled. Multiplex ligation-dependent probe amplification was used to measure the gene copy numbers of SMN1 and SMN2. The association of copy number of SMN1 and SMN2 with clinical phenotypes was analyzed. Results Of the 45 children with SMA,42(93%) had a homozygous deletion of SMN1 exons 7 and 8, and 3(7%) had a deletion of SMN1 exon 7 alone. No association was found between SMA clinical types and the deletion types of SMN1 exons 7 and 8(P>0.05). There was a significant difference in the distribution of SMN2 gene copy numbers between the children with SMA and the healthy children(P<0.05). The children with SMA usually had two or three copies of SMN2 gene, while the healthy children usually had one or two copies of SMN2 gene. There was a significant difference in the distribution of SMN2 copy numbers among the children with different SMA clinical types(P <0.05). The children with two copies of SMN2 gene had a significantly lower age of onset than those with three or four copies. Most of the children with type I SMA had two or three copies of SMN2 gene. Most of the children with type II SMA had three copies of SMN2 gene. Most of the children with type III SMA had three or four copies of SMN2 gene. Children with a higher copy number of SMN2 gene tended to have an older age of onset and better motor function and clinical outcome, and there was a significant association between SMN2 gene copy number and clinical outcome(P<0.05). Conclusions The SMN2 gene can reduce the severity of SMA via the dosage compensation effect. SMN2 copy number is associated with the phenotype of SMA, and therefore, it can be used to predict disease severity.
引文
[1]Prior TW,Snyder PJ,Rink BD,et al.Newborn and carrier screening for spinal muscular atrophy[J].Am J Med Genet A,2010,152A(7):1608-1616.
[2]Sheng-Yuan Z,Xiong F,Chen YJ,etal.Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population[J].Eur J Hum Genet,2010,18(9):978-984.
[3]杨兰,宋昉.脊髓性肌萎缩症的治疗研究进展[J].中华儿科杂志,2016,54(8):634-637.
[4]Verhaart IEC,Robertson A,Wilson IJ,et al.Prevalence,incidence and carrier frequency of 5q-linked spinal muscular atrophy-a literature review[J].Orphanet J Rare Dis,2017,12(1):124.
[5]Faravelli I,Nizzardo M,Comi GP,et al.Spinal muscular atrophy--recent therapeutic advances for an old challenge[J].Nat Rev Neurol,2015,11(6):351-359.
[6]Arnold WD,Kassar D,Kissel JT.Spinal muscular atrophy:diagnosis and management in a new therapeutic era[J].Muscle Nerve,2015,51(2):157-167.
[7]Farrar MA,Park SB,Vucic S,et al.Emerging therapies and challenges in spinal muscular atrophy[J].Ann Neurol,2017,81(3):355-368.
[8]张蕾,颉小玲,李娟,等.脊髓性肌萎缩症遗传学及治疗研究进展[J].临床儿科杂志,2017,35(8):632-635.
[9]Munsat TL,Davies KE.International SMA consortium meeting.(26-28 June 1992,Bonn,Germany)[J].Neuromuscul Disord,1992,2(5-6):423-428.
[10]HachéM,Swoboda KJ,Sethna N,et al.Intrathecal injections in children with spinal muscular atrophy:nusinersen clinical trial experience[J].J Child Neurol,2016,31(7):899-906.
[11]Pechmann A,Langer T,Wider S,et al.Single-center experience with intrathecal administration of Nusinersen in children with spinal muscular atrophy type 1[J].Eur J Paediatr Neurol,2018,22(1):122-127.
[12]He J,Zhang QJ,Lin QF,et al.Molecular analysis of SMN1,SMN2,NAIP,GTF2H2,and H4F5 genes in 157 Chinese patients with spinal muscular atrophy[J].Gene,2013,518(2):325-329.
[13]Fang P,Li L,Zeng J,et al.Molecular characterization and copy number of SMN1,SMN2 and NAIP in Chinese patients with spinal muscular atrophy and unrelated healthy controls[J].BMCMusculoskelet Disord,2015,16(1):11.
[14]刘维亮,李芳,麻宏伟,等.中国脊髓性肌萎缩症患儿的SMN基因学研究[J].中国当代儿科杂志,2010,12(7):539-543.
[15]卢丽萍,麻宏伟,姜俊,等.脊髓性肌萎缩临床表型与SMN2基因拷贝数变化的相关性研究[J].中华医学遗传学杂志,2007,24(2):144-147.
[16]Qu YJ,Ge XS,Bai JL,et al.Association of copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein gene with the natural history in a Chinese spinal muscular atrophy cohort[J].J Child Neurol,2015,30(4):429-436.
[17]Butchbach ME.Copy number variations in the survival motor neuron genes:implications for spinal muscular atrophy and other neurodegenerative diseases[J].Front Mol Biosci,2016,3:7.
[18]王佶,安宇,周水珍,等.脊髓性肌萎缩症SMN1和SMN2基因拷贝数变异分析[J].中国循证儿科杂志,2013,8(3):216-219.
[19]Glascock J,Sampson J,Haidet-Phillips A,et al.Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening[J].J Neuromuscul Dis,2018,5(2):145-158.
[20]Prior TW,Swoboda KJ,Scott HD,et al.Homozygous SMN1deletions in unaffected family members and modification of the phenotype by SMN2[J].Am J Med Genet A,2004,130A(3):307-310.
[21]Ahn EJ,Yum MS,Kim EH,et al.Genotype-phenotype correlation of SMN1 and NAIP deletions in Korean patients with spinal muscular atrophy[J].J Clin Neurol,2017,13(1):27-31.
[22]Nishio H.PLS3 expression and SMA phenotype:a commentary on correlation of PLS3 expression with disease severity in children with spinal muscular atrophy[J].J Hum Genet,2014,59(2):64-65.
[23]Strathmann EA,Peters M,Hosseinibarkooie S,et al.Evaluation of potential effects of Plastin 3 overexpression and low-dose SMN-antisense oligonucleotides on putative biomarkers in spinal muscular atrophy mice[J].PLoS One,2018,13(9):e0203398.
[24]Hosseinibarkooie S,Peters M,Torres-Benito L,et al.The power of human protective modifiers:PLS3 and CORO1C unravel impaired endocytosis in spinal muscular atrophy and rescue SMA phenotype[J].Am J Hum Genet,2016,99(3):647-665.
[25]Riessland M,Kaczmarek A,Schneider S,et al.Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis[J].Am J Hum Genet,2017,100(2):297-315.
[2]Sheng-Yuan Z,Xiong F,Chen YJ,etal.Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population[J].Eur J Hum Genet,2010,18(9):978-984.
[3]杨兰,宋昉.脊髓性肌萎缩症的治疗研究进展[J].中华儿科杂志,2016,54(8):634-637.
[4]Verhaart IEC,Robertson A,Wilson IJ,et al.Prevalence,incidence and carrier frequency of 5q-linked spinal muscular atrophy-a literature review[J].Orphanet J Rare Dis,2017,12(1):124.
[5]Faravelli I,Nizzardo M,Comi GP,et al.Spinal muscular atrophy--recent therapeutic advances for an old challenge[J].Nat Rev Neurol,2015,11(6):351-359.
[6]Arnold WD,Kassar D,Kissel JT.Spinal muscular atrophy:diagnosis and management in a new therapeutic era[J].Muscle Nerve,2015,51(2):157-167.
[7]Farrar MA,Park SB,Vucic S,et al.Emerging therapies and challenges in spinal muscular atrophy[J].Ann Neurol,2017,81(3):355-368.
[8]张蕾,颉小玲,李娟,等.脊髓性肌萎缩症遗传学及治疗研究进展[J].临床儿科杂志,2017,35(8):632-635.
[9]Munsat TL,Davies KE.International SMA consortium meeting.(26-28 June 1992,Bonn,Germany)[J].Neuromuscul Disord,1992,2(5-6):423-428.
[10]HachéM,Swoboda KJ,Sethna N,et al.Intrathecal injections in children with spinal muscular atrophy:nusinersen clinical trial experience[J].J Child Neurol,2016,31(7):899-906.
[11]Pechmann A,Langer T,Wider S,et al.Single-center experience with intrathecal administration of Nusinersen in children with spinal muscular atrophy type 1[J].Eur J Paediatr Neurol,2018,22(1):122-127.
[12]He J,Zhang QJ,Lin QF,et al.Molecular analysis of SMN1,SMN2,NAIP,GTF2H2,and H4F5 genes in 157 Chinese patients with spinal muscular atrophy[J].Gene,2013,518(2):325-329.
[13]Fang P,Li L,Zeng J,et al.Molecular characterization and copy number of SMN1,SMN2 and NAIP in Chinese patients with spinal muscular atrophy and unrelated healthy controls[J].BMCMusculoskelet Disord,2015,16(1):11.
[14]刘维亮,李芳,麻宏伟,等.中国脊髓性肌萎缩症患儿的SMN基因学研究[J].中国当代儿科杂志,2010,12(7):539-543.
[15]卢丽萍,麻宏伟,姜俊,等.脊髓性肌萎缩临床表型与SMN2基因拷贝数变化的相关性研究[J].中华医学遗传学杂志,2007,24(2):144-147.
[16]Qu YJ,Ge XS,Bai JL,et al.Association of copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein gene with the natural history in a Chinese spinal muscular atrophy cohort[J].J Child Neurol,2015,30(4):429-436.
[17]Butchbach ME.Copy number variations in the survival motor neuron genes:implications for spinal muscular atrophy and other neurodegenerative diseases[J].Front Mol Biosci,2016,3:7.
[18]王佶,安宇,周水珍,等.脊髓性肌萎缩症SMN1和SMN2基因拷贝数变异分析[J].中国循证儿科杂志,2013,8(3):216-219.
[19]Glascock J,Sampson J,Haidet-Phillips A,et al.Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening[J].J Neuromuscul Dis,2018,5(2):145-158.
[20]Prior TW,Swoboda KJ,Scott HD,et al.Homozygous SMN1deletions in unaffected family members and modification of the phenotype by SMN2[J].Am J Med Genet A,2004,130A(3):307-310.
[21]Ahn EJ,Yum MS,Kim EH,et al.Genotype-phenotype correlation of SMN1 and NAIP deletions in Korean patients with spinal muscular atrophy[J].J Clin Neurol,2017,13(1):27-31.
[22]Nishio H.PLS3 expression and SMA phenotype:a commentary on correlation of PLS3 expression with disease severity in children with spinal muscular atrophy[J].J Hum Genet,2014,59(2):64-65.
[23]Strathmann EA,Peters M,Hosseinibarkooie S,et al.Evaluation of potential effects of Plastin 3 overexpression and low-dose SMN-antisense oligonucleotides on putative biomarkers in spinal muscular atrophy mice[J].PLoS One,2018,13(9):e0203398.
[24]Hosseinibarkooie S,Peters M,Torres-Benito L,et al.The power of human protective modifiers:PLS3 and CORO1C unravel impaired endocytosis in spinal muscular atrophy and rescue SMA phenotype[J].Am J Hum Genet,2016,99(3):647-665.
[25]Riessland M,Kaczmarek A,Schneider S,et al.Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis[J].Am J Hum Genet,2017,100(2):297-315.