Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy:: three SMN2 copies fail to rescue some patients from the disease severity
Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy:: three SMN2 copies fail to rescue some patients from the disease severity
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DOI：
10.1007/s00415-002-0811-4
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发表时间：
2002-09-01
影响因子：
6
通讯作者：
Nishio, H
中科院分区：
文献类型：
--
作者：
Harada, Y;Sutomo, R;Nishio, H
脊髓性肌萎缩症（spinal muscular atrophy，SMA）是一种常见的常染色体隐性遗传性神经肌肉疾病，其特征是脊髓前角细胞变性，导致与肌肉萎缩相关的轴性和肢体无力。SMA根据临床严重程度分为三组：I型（重度）、II型（中度）和III型（轻度）。SMA的所有三种临床亚型均由SMN 1基因突变引起。超过95%的SMA患者显示SMN 1纯合缺失。据认为，SMN 2是SMN 1的高度同源基因，在一定程度上补偿了SMN 1的缺失。为了阐明SMN 2与SMA疾病严重程度之间的关系，我们对27例SMN 1缺失纯合子患者（11例I型和16例II-III型）的SMN 2拷贝数进行了基于荧光的定量聚合酶链反应分析。II-III型患者的SMN 2拷贝数为3.1 +/- 0.3（平均值+/- SD），显著高于I型患者的2.2 +/- 0.6（P < 0.01）。然而，11例I型患者中有3例携带3个SMN 2拷贝。进一步研究了具有3个SMN 2拷贝的I型患者。患者的RT-PCR分析显示痕量全长SMN 2 mRNA种类，但大量缺失外显子7的截短SMN 2 mRNA种类。总之，SMA患者的SMN 2等位基因在功能上并不等同，尽管一般而言SMN 2拷贝数与SMA的严重程度相关。影响SMN 2基因剪接机制的遗传背景在某些SMA患者中可能更为关键。
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is characterized by degeneration of the anterior horn cells of the spinal cord, which leads to the axial and limb weakness associated with muscle atrophy. SMA is classified into three groups based on the clinical severity: type I (severe), type II (intermediate) and type III (mild). All three clinical subtypes of SMA are caused by mutations of the SMN1 gene. More than 95% of SMA patients show homozygous deletion of SMN1. It is thought that SMN2, which is a highly homologous gene of SMN1, compensates for the SMN1 deletion to some degree. To clarify the relationship between SMN2 and the disease severity of SMA, we performed fluorescence-based quantitative polymerase chain reaction assay of the copy number of SMN2 in 27 patients (11 type I and 16 type II-III) homozygous for SMN1 deletion. The SMN2 copy number in type II-III patients was 3.1 +/- 0.3 (mean +/- SD), which is significantly higher than that observed in type I patients, 2.2 +/- 0.6 (P < 0.01). However, three of the 11 type I patients carried 3 SMN2 copies. A type I patient with 3 SMN2 copies was studied further. RT-PCR analysis of the patient showed a trace of full-length SMN2 mRNA species, but a large amount of the truncated SMN2 mRNA species lacking exon 7. In conclusion, SMN2 alleles are not functionally equivalent among SMA patients, although in general the SMN2 copy number is correlated with the severity of SMA. Genetic background influencing splicing mechanisms of the SMN2 gene may be more critical in some SMA patients.