Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development

被引:58
作者
Butchbach, Matthew E. R. [1 ,2 ,3 ,4 ]
机构
[1] Nemours Childrens Hlth Delaware, Ctr Appl Clin Genom, Wilmington, DE 19803 USA
[2] Nemours Childrens Hlth Delaware, Ctr Pediat Res, Wilmington, DE 19803 USA
[3] Univ Delaware, Dept Biol Sci, Newark, DE 19716 USA
[4] Thomas Jefferson Univ, Dept Pediat, Philadelphia, PA 19107 USA
关键词
spinal muscular atrophy; copy number variation; SMN1; SMN2; modifier gene; precision medicine; therapeutics; gene conversion; hybrid gene; DEPENDENT PROBE AMPLIFICATION; APOPTOSIS INHIBITORY PROTEIN; LARGE-SCALE DELETIONS; PLASTIN; EXPRESSION; COPY-NUMBER; SMA PATIENTS; MOLECULAR ANALYSIS; MESSENGER-RNA; MISSENSE MUTATION; DISEASE SEVERITY;
D O I
10.3390/ijms22157896
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1-SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.
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页数:22
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