Wirth Brunhilde, Brichta Lars, Hahnen Eric
Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Semin Pediatr Neurol. 2006 Jun;13(2):121-31. doi: 10.1016/j.spen.2006.06.008.
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.
脊髓性肌萎缩症（SMA）是一种常染色体隐性神经肌肉疾病，其分子基础是生存运动神经元基因1（SMN1）的纯合缺失。SMN1基因有一个几乎相同的拷贝，称为SMN2，它可调节疾病的严重程度。这两个基因之间的功能差异是一个翻译沉默突变，但它会破坏一个外显子剪接增强子，导致大多数SMN2转录本中的外显子7跳跃。只有10%的SMN2转录本编码与SMN1相同的功能性全长蛋白。转录激活、促进正确的SMN2剪接或蛋白质的稳定被认为是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-苯丁酸（PBA）已被证明可提高SMN2衍生的RNA和蛋白质水平。最近，在接受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。
