Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases.
Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases.
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DOI：
10.3389/fmolb.2016.00007
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发表时间：
2016
影响因子：
5
通讯作者：
Butchbach ME
中科院分区：
文献类型：
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作者：
Butchbach ME
近端脊髓性肌萎缩症（SMA）是一种早发性常染色体隐性遗传性神经退行性疾病，其特征是脊髓α运动神经元缺失，是全球婴儿死亡的主要遗传原因。这种α运动神经元的丧失与肌肉无力和萎缩有关。SMA可根据发病年龄和疾病严重程度分为五个临床等级。无论临床分级如何，近端SMA均由染色体5 q13上的SMN 1（运动神经元存活1）缺失或突变引起。在人类中，一个大的串联染色体复制导致了SMN基因位点的第二个拷贝，称为SMN 2。SMN 2可通过破坏外显子7中外显子剪接增强子的单核苷酸差异与SMN 1区分。因此，大多数SMN 2 mRNA缺乏外显子7（SMNΔ7），并产生一种不稳定且功能不全的蛋白质。虽然只有10-20%的SMN 2基因产物具有完全功能，但SMN 2基因组拷贝数增加与SMA患者的疾病严重程度呈负相关。由于SMN 2拷贝数影响SMA的疾病严重程度，因此准确测量接受SMA评价的患者的SMN 2拷贝数具有预后价值。鉴于SMN 2拷贝数目前被用作SMA临床试验的入选标准，该预后价值尤为重要。除SMA外，SMN基因中的拷贝数变异（CNV）可影响其他神经系统疾病的临床严重程度，包括肌萎缩性侧索硬化（ALS）和进行性肌萎缩（PMA）。本综述将讨论如何检测SMN 1和SMN 2 CNV，以及为什么准确测量SMN 1和SMN 2拷贝数与SMA和其他神经退行性疾病相关。
Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10–20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases.