Spinal muscular atrophy: from gene to therapy.
Spinal muscular atrophy: from gene to therapy.
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DOI：
10.1016/j.spen.2006.06.008
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发表时间：
2006-06-01
影响因子：
2.7
通讯作者：
Hahnen, Eric
中科院分区：
文献类型：
--
作者：
Wirth, Brunhilde;Brichta, Lars;Hahnen, Eric
脊髓性肌萎缩症（SMA）是一种常染色体隐性遗传性神经肌肉疾病，其分子基础是运动神经元存活基因1（SMN 1）的纯合缺失。SMN 1基因的一个几乎相同的拷贝，称为SMN 2，调节疾病的严重程度。这两种基因之间的功能差异是一种功能性沉默突变，然而，该突变破坏了外显子剪接增强子，导致大多数SMN 2转录物中的外显子7跳跃。只有10%的SMN 2转录物编码与SMN 1相同的功能全长蛋白。转录激活、促进正确的SMN 2剪接或稳定蛋白质被认为是SMA治疗的策略。在各种药物中，组蛋白脱乙酰酶抑制剂如丙戊酸（VPA）或4-苯基丁酸（PBA）已被证明可增加SMN 2衍生的RNA和蛋白质水平。最近，在VPA治疗的SMA患者和携带者中显示了SMN基因的体内激活。正在进行临床试验，以研究VPA和PBA对SMA患者运动功能的影响。
The molecular basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the homozygous loss of the survival motor neuron gene 1 (SMN1). A nearly identical copy of the SMN1 gene, called SMN2, modulates the disease severity. The functional difference between both genes is a translationally silent mutation that, however, disrupts an exonic splicing enhancer causing exon 7 skipping in most SMN2 transcripts. Only 10% of SMN2 transcripts encode functional full-length protein identical to SMN1. Transcriptional activation, facilitation of correct SMN2 splicing, or stabilization of the protein are considered as strategies for SMA therapy. Among various drugs, histone deacetylase inhibitors such as valproic acid (VPA) or 4-phenylbutyrate (PBA) have been shown to increase SMN2-derived RNA and protein levels. Recently, in vivo activation of the SMN gene was shown in VPA-treated SMA patients and carriers. Clinical trials are underway to investigate the effect of VPA and PBA on motor function in SMA patients.