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Review
. 2021 Jul 23;22(15):7896.
doi: 10.3390/ijms22157896.

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

Matthew E R Butchbach  1   2   3   4
Affiliations
Review

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

Matthew E R Butchbach. Int J Mol Sci. .

Abstract

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.

Keywords: SMN1; SMN2; copy number variation; gene conversion; hybrid gene; modifier gene; precision medicine; spinal muscular atrophy; therapeutics.

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Conflict of interest statement

The author declares no conflict of interest. The funders had no role in the writing of the manuscript or in the decision to publish the review.

Figures

Figure 1
Figure 1
Genomic organization of the SMA-associated segmental duplication at chromosome 5q13 and the functional differences between SMN1 and SMN2 with respect to SMN gene regulation. Adapted from [42,43].
Figure 2
Figure 2
Relationship between SMN1–SMN2 gene conversion and disease severity in SMA. Adapted from [134].
Figure 3
Figure 3
Paralogous sequence variants (PSVs) between SMN1 and SMN2. The canonical PSV at exon 7 that functionally distinguishes SMN1 from SMN2 is highlighted in green.
Figure 4
Figure 4
Location of SMA-associated intragenic missense and nonsense mutations within SMN1 relative to protein domain location. The mutated residues in red are nonsense mutations while those in black are missense mutations. Adapted from [48].
Figure 5
Figure 5
Allelic organizations of SMN1 copies within normal (SMN1:1+1), silent carrier (SMN1:2+0), carrier (SMN1:1+0) and SMA (SMN1:0+0) patients.
See this image and copyright information in PMC

References

    1. Crawford T.O., Pardo C.A. The neurobiology of childhood spinal muscular atrophy. Neurobiol. Dis. 1996;3:97–110. doi: 10.1006/nbdi.1996.0010. - DOI - PubMed
    1. Kolb S.J., Kissel J.T. Spinal muscular atrophy. Neurol. Clin. 2015;33:831–846. doi: 10.1016/j.ncl.2015.07.004. - DOI - PMC - PubMed
    1. Cuscó I., Barceló M.J., Soler C., Parra J., Baiget M., Tizzano E. Prenatal diagnosis for risk of spinal muscular atrophy. Br. J. Obstet. Gynaecol. 2002;109:1244–1249. doi: 10.1016/S1470-0328(02)02983-X. - DOI - PubMed
    1. Pearn J. Incidence, prevalence and gene frequency studies of chronic childhood spinal muscular atrophy. J. Med. Genet. 1978;15:409–413. doi: 10.1136/jmg.15.6.409. - DOI - PMC - PubMed
    1. Sugarman E.A., Nagan N., Zhu H., Akmaev V.R., Zhou Z., Rohlfs A.M., Flynn K., Hendrickson B.C., Scholl T., Sirko-Osadsa D.A., et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of > 72400 specimens. Eur. J. Hum. Genet. 2012;20:27–32. doi: 10.1038/ejhg.2011.134. - DOI - PMC - PubMed

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