Abstract
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.
Introduction
Proximal spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide, alongside cystic fibrosis. The incidence of SMA is 1 in 6000–10,000 live births (Pearn, 1978; Cuscó et al., 2002; Sugarman et al., 2012). The carrier frequency for SMA is 1:25–50 in most populations (Ben-Shachar et al., 2011; Su et al., 2011; Lyahyai et al., 2012; Sugarman et al., 2012) though it is lower for some ethnicities (Zaldívar et al., 2005; Labrum et al., 2007; Hendrickson et al., 2009; Sangaré et al., 2014).
SMA is an early-onset neurodegenerative disease characterized by the loss of α-motor neurons in the anterior horn of the spinal cord, i.e., lower motor neurons (LMNs; Crawford and Pardo, 1996; Kolb and Kissel, 2015). This loss of α-motor neurons is associated with muscle weakness and atrophy. In SMA, those muscles that are proximally innervated are preferentially affected over distal muscles. SMA can be classified into five clinical grades based on age of onset and severity of the disease (Munsat and Davies, 1992; Russman, 2007; Table 1). Type 0 SMA infants present with very severe hypotonia and require respiratory support from birth. These SMA infants cannot survive beyond 6 months. Type I SMA [listed in the Online Inheritance in Man (OMIM) database under accession number 253300; http://www.omim.org/entry/253300] patients have an age of onset before 6 months. They show hypotonia and weakness in limbs; they are unable to sit independently. Type I SMA infants show a bell-shaped chest due to weakness in the intercostals muscles but sparing of the diaphragm; this bell-shaped chest results in abnormal breathing patterns. These patients typically live < 2 years. Type II SMA (http://www.omim.org/entry/253500) patients have an age of onset before 18 months. They are poor crawlers and weak sitters; most of these patients can rarely stand and only with support. Their legs are generally weaker than their arms. Due in part to better supportive care, these patients generally have a life expectancy into early adulthood. Type III SMA (http://www.omim.org/entry/253400) patients have an age of onset >18 months. These patients are able to walk with difficulty (waddling gait) and the legs are weaker than the arms. Type III patients usually have a normal lifespan. Adult-onset (type IV) SMA (http://www.omim.org/entry/271150) patients have an age of onset of 18–21 years. Type IV SMA exhibits as a slowly progressive limb weakness. The disease is fairly benign in these patients.
Table 1
| Type | Age of onset | Requires respiratory support at birth | Able to sit | Able to stand | Able to walk | Life expectancy | Predicted SMN2 copy number |
|---|---|---|---|---|---|---|---|
| 0 | Prenatal | Yes | No | No | No | <6 months | 1 |
| 1 | <6 months | No | No | No | No | <2 years | 2 |
| 2 | 6–18 months | No | Yes | No | No | 10–40 years | 3 |
| 3 | >18 months | No | Yes | Yes | Assisted | Adult | 3–4 |
| 4 | >5 years | No | Yes | Yes | Yes | Adult | >4 |
Clinical classification of spinal muscular atrophy (SMA).
Genetics of SMA
SMA is an autosomal recessive disorder (Brandt, 1949). Linkage analysis (Brzustowicz et al., 1990; Gilliam et al., 1990; Melki et al., 1990a,b) along with genetic and physical mapping studies (reviewed in Morrison, 1996) identified the SMA locus on the long arm of chromosome 5, specifically in the 5q13 region. There is a 500 kilobase (kb) inverted segmental duplication within this region of chromosome 5 that is unique to humans (Courseaux et al., 2003; Schmutz et al., 2004). Four protein-coding genes have been identified within this region (Figure 1): SMN1 [survival motor neuron 1, telomeric SMN (SMNT; Lefebvre et al., 1995)], NAIP [neuronal apoptosis inhibitor protein (Roy et al., 1995)], GTF2H2A [general transcription factor IIH, p44 (Bürglen et al., 1997; Carter et al., 1997)], and SERF1A [small EDRK-rich factor 1A, H4F5A (Scharf et al., 1998)]. The duplicated genes are either identical to their partner gene (SERF1B), different in a small number of nucleotides [SMN2 or centromeric SMN (SMNC)] or are pseudogenes (ΨGTF2H2B and ΨNAIPΔ5).
Figure 1
In more than 95% of cases, proximal SMA results from the loss of SMN1 but retention of SMN2, regardless of clinical grade (Lefebvre et al., 1995). Large-scale deletions in chromosome 5q13 that include SMN1, NAIP, SERF1A, and GTF2H2A are observed in patients with type I SMA (Wirth et al., 1995; Burlet et al., 1996; Rodrigues et al., 1996; Velasco et al., 1996; Bürglen et al., 1997; Carter et al., 1997). Smaller deletions only involving SMN1 have also been observed in type I SMA patients demonstrating that SMN1 is the most likely causative gene for SMA. In addition, the identification of intragenic SMA mutations in SMN1 (Lefebvre et al., 1995; see Burghes and Beattie, 2009 for a comprehensive listing of SMA-associated point mutations in SMN1) provides additional evidence to support SMN1 as the gene responsible for SMA. To date, no intragenic mutations in the other genes within this segmental duplication have been associated with SMA.
As mentioned earlier, the SMN gene is duplicated in humans to give rise to SMN1 and SMN2. This duplication of SMN is unique to humans (Rochette et al., 2001). What is the difference between SMN1 and SMN2? The major difference between these two SMN genes is a C-to-T transition in exon 7(SMN2 c.850C>T; Lorson et al., 1999; Monani et al., 1999). This nucleotide change is translationally silent. This position on exon 7 is in the middle of an exonic splicing enhancer (ESS) sequence that regulated the inclusion of exon 7 in SMN transcripts (Figure 2). For SMN1, the C at this position promotes inclusion of exon 7 in SMN1-derived mRNAs which leads to the production of full-length SMN protein. Full-length SMN protein is able to form functional complexes. For SMN2, the T at this position disrupts this ESS which results in the exclusion of exon 7 (SMNΔ7) from the majority of SMN2-derived mRNAs. As a result, a truncated SMNΔ7 protein is produced by the majority (~90%) of SMN2-derived mRNAs; this SMNΔ7 protein is unstable and is unable to associate with itself (Lorson and Androphy, 2000; Burnett et al., 2009; Cho and Dreyfuss, 2010). The SMNΔ7 protein is still partially functional given that transgenic overexpression of SMNΔ7 in severe SMA mice partially ameliorates their phenotype since these mice die at 14–15 days as opposed to 5–8 days (Le et al., 2005). About 10% of the mRNAs from SMN2 contain exon 7 and these full-length mRNAs can produce some full-length, functional SMN protein.
Figure 2
Biology of SMN
SMN is a ubiquitously expressed protein whose expression is reduced in SMA. There is a strong inverse correlation between SMN protein levels and disease severity in SMA fibroblasts and lymphoblastoid cells as well (Coovert et al., 1997; Lefebvre et al., 1997; Kolb et al., 2006). Changes in SMN mRNA and protein levels observed in SMA patient-derived PBMCs mirror those observed in SMA cell lines (Sumner et al., 2006; Simard et al., 2007; Vezain et al., 2007; Tiziano et al., 2010; Crawford et al., 2012). SMN protein is present within the nuclei in discreet foci known as gems (Liu and Dreyfuss, 1996). In SMA fibroblasts, the number of SMN-positive subnuclear gems is higher in cells derived from mild SMA individuals than in those from children with more severe forms of SMA (Coovert et al., 1997).
SMN is required for the assembly of the small nuclear ribonucleoprotein (snRNP) complexes that mediate splicing (Pellizzoni, 2007; Burghes and Beattie, 2009). snRNP assembly is defective in SMN-deficient SMA cells (Wan et al., 2005). Since snRNP assembly is required for all cell types, why are motor neurons primarily affected in SMA? snRNP assembly is defective in tissues from mouse models for SMA and that the extent of reduced snRNP assembly correlates with phenotypic severity of these SMA mice (Gabanella et al., 2005; Zhang et al., 2008). snRNP assembly is more markedly reduced in SMA mouse neural tissues than in other tissues like the kidney (Gabanella et al., 2005) suggesting that motor neurons are more sensitive to deficits in snRNP assembly. SMN may also have a function that is unique to motor neurons. Axonal defects in Smn-knocked down zebrafish embryos (McWhorter et al., 2003) are corrected by overexpression of mutant SMNs which are incapable of snRNP assembly (Carrel et al., 2006).
SMN2 CNV in SMA
The number of SMN2 copies in the genome varies between 0 and 8. Numerous studies have demonstrated an inverse relationship between SMN2 copy number and disease severity among in SMA (Lefebvre et al., 1995, 1997; van der Steege et al., 1995; Coovert et al., 1997; McAndrew et al., 1997; Taylor et al., 1998; Feldkötter et al., 2002; Mailman et al., 2002; Anhuf et al., 2003; Gérard et al., 2004; Prior et al., 2005; Su et al., 2005; Swoboda et al., 2005; Arkblad et al., 2006; Scarciolla et al., 2006; Wirth et al., 2006; Gómez-Curet et al., 2007; Huang et al., 2007; Tiziano et al., 2007; Elsheikh et al., 2009; Wang et al., 2010a,b, 2014a; Alías et al., 2011; Amara et al., 2012; Crawford et al., 2012; Dobrowolski et al., 2012; Kirwin et al., 2013; Qu et al., 2014; Brkušanin et al., 2015; Fang et al., 2015; Stabley et al., 2015). Patients with milder forms of SMA have higher SMN2 copy numbers than severe SMA patients (Table 1).
Mice have only 1 SMN gene, mSmn, which is orthologous to SMN1 (DiDonato et al., 1997a; Viollet et al., 1997). Loss of mSmn leads to embryonic lethality (Schrank et al., 1997). Conditional loss of mSmn in specific cell types like neurons, myofibers and hepatocytes results in loss of those cells in vivo (Cifuentes-Diaz et al., 2002; Nicole et al., 2003; Vitte et al., 2004). Transgenic insertion of SMN2 rescues the embryonic lethality observed in mSmn nullizygous mice (Hsieh-Li et al., 2000; Monani et al., 2000; Michaud et al., 2010). While two copies of SMN2 rescues embryonic lethality in mSmn-deficient mice, these mice develop a very severe motor phenotype and die within 8 days after birth (Hsieh-Li et al., 2000; Monani et al., 2000). Those mSmn-deficient mice with 3-4 SMN2 copies exhibit a milder SMA phenotype than the two copy SMN2 SMA mice (Hsieh-Li et al., 2000; Michaud et al., 2010). If the SMN2 copy number is high (i.e., 8), then the resultant mSmn-deficient mice exhibit no signs of SMA and are phenotypically normal (Monani et al., 2000). SMN2 CNV, therefore, is a major modifier of disease severity in SMA in mice as well as in humans.
Gene conversion is one mechanism to account for increased SMN2 copy number in the absence of SMN1 in SMA (Burghes, 1997). In this scenario, the SMN1 gene actually contains part of SMN2, in particular within exon 7 (Wirth et al., 1995; Devriendt et al., 1996; Hahnen et al., 1996; van der Steege et al., 1996; Campbell et al., 1997; DiDonato et al., 1997b). It is hypothesized that type I SMA patients have deletions of SMN1 on both chromosomes. Type II SMA patients have an SMN1 deletion on one chromosome and a SMN1-to-SMN2 conversion on the other chromosome (three copies of SMN2). Type III SMA patients have SMN1-to-SMN2 converted genes on both chromosomes (four copies).
While the inverse relationship between SMN2 copy number and disease severity generally holds true in SMA, there are some exceptions. For example, there are cases of type II and III SMA patients who harbor only two copies of SMN2 instead of the predicted three or four copies (Prior et al., 2009; Bernal et al., 2010; Vezain et al., 2010). Sequencing of SMN2 in these cases revealed the presence of a rare single nucleotide variant (SMN2 c.859G>C) in exon 7 (Prior et al., 2009; Bernal et al., 2010; Vezain et al., 2010). This variant regulates the splicing of SMN2 pre-mRNAs so that a greater proportion of SMN2 transcripts contain exon 7. This variant may either create an additional SF2/ASF binding to promote exon 7 inclusion (Prior et al., 2009) or disrupt a hnRNPA1-dependent splicing silencer element (Vezain et al., 2010).
Intrafamilial variability in clinical presentation has been reported in SMA families with more than one affected sibling (Burghes et al., 1994; Cobben et al., 1995; Hahnen et al., 1995; McAndrew et al., 1997; Cuscó et al., 2006). Even though the siblings are haploidentical with respect to SMN2 copy number, they have differing clinical presentations. This would suggest that there are SMN2-independent modifiers of disease severity for SMA. Plastin-3 (PLS3) mRNA levels were higher in females with milder SMA than in discordant siblings with a more severe SMA clinical presentation (Oprea et al., 2008; Stratigopoulos et al., 2010; Bernal et al., 2011; Yanyan et al., 2014). In some families, however, female siblings with a more severe SMA phenotype show high PLS3 mRNA levels (Bernal et al., 2011). It is possible that the modifier property of PLS3 is age- and sex-dependent as well as incompletely penetrant; alternatively, PLS3 may not actually be a major modifier of SMA phenotype. There may be other non-SMN2 molecular modifiers of disease severity in SMA. It is important to identify and characterize these novel modifiers for the development of novel SMA biomarkers and targets for the development of therapeutic strategies for SMA as well as for the planning of current and future clinical trials in SMA (Wirth et al., 2013).
Measuring SMN1 and SMN2 CNVs
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. Molecular diagnosis of SMA— i.e., loss of SMN1—has historically been made using a polymerase chain reaction (PCR)-based assay followed by digestion of the PCR product with specific restriction endonucleases (PCR-RFLP; Lefebvre et al., 1995; van der Steege et al., 1995). Numerous assays have since been developed to quantify SMN2 copy number in DNA samples from SMA patients. These assays include radioactive PCR (Coovert et al., 1997; McAndrew et al., 1997), fluorescent PCR (Taylor et al., 1998), quantitative (real-time) PCR (qPCR; Feldkötter et al., 2002; Anhuf et al., 2003; Gómez-Curet et al., 2007), competitive PCR/primer extension (Gérard et al., 2004), denaturing high performance liquid chromatography (Su et al., 2005), multiplex ligation-dependent probe amplification (MLPA; Arkblad et al., 2006; Scarciolla et al., 2006; Huang et al., 2007; Alías et al., 2011; Fang et al., 2015), quantitative capillary electrophoresis fragment analysis (Kirwin et al., 2013), short-amplicon melt profiling (Dobrowolski et al., 2012), fluorescent multiplex PCR/capillary electrophoresis (Wang et al., 2010a,b), and universal fluorescent triprobe ligation (Wang et al., 2014a). An important limitation of these established PCR-based copy number assays is the requirement for a parallel-run calibration curve to assign a breakpoint necessary that identifies placement of an ordinal SMN2 value. Additionally, these techniques cannot easily distinguish unit differences in SMN1 or SMN2 when the copy number is >3 (Gómez-Curet et al., 2007; Alías et al., 2011; Prior et al., 2011).
To overcome some of the limitations associated with the PCR-based assays described above, digital PCR (dPCR) distributed across a large number of partitions by limited dilution so that some partitions will lack the template DNA (Sykes et al., 1992; Vogelstein and Kinzler, 1999). The absolute abundance of the target gene can be measured by counting the number of positive partitions and the number of negative partitions. dPCR can reliably and accurately measure SMN1 and SMN2 copy numbers over a wide range, i.e., between 0 and 6 copies (Zhong et al., 2011; Stabley et al., 2015).
SMN1 and SMN2 CNVs in ALS
Amyotrophic lateral sclerosis (ALS) is a mostly adult-onset motor neuron disease characterized by a progressive loss of motor function leading to paralysis and respiratory failure (Boylan, 2015; Statland et al., 2015). Unlike SMA, ALS is caused by degeneration of LMNs as well as upper motor neurons (UMNs). ALS is usually fatal within 3–5 years after disease onset but there is considerable variability with respect to duration as well as phenotypic presentation (Swinnen and Robberecht, 2014). Most cases of ALS are sporadic in nature since there is no apparent family history. Approximately 10% of ALS is considered familial since either a causative gene has been identified or there is strong family history. With the recent advents of whole exome and whole genome sequencing, the genetic bases of almost 70% of familial ALS and 10% of sporadic ALS have been identified (Renton et al., 2014).
There are many case studies reporting the co-occurrence of SMA and ALS within a family (Appelbaum et al., 1992; Camu and Billiard, 1993; Orrell et al., 1997; Corcia et al., 2002a) which suggests that SMN1 deficiency may lead to ALS in addition to SMA. SMN1 deletions, however, have not been observed in either familial or sporadic ALS patients (Orrell et al., 1997; Corcia et al., 2002a). Furthermore, no intragenic point mutations in SMN1 have been reported in the ALS population (Blauw et al., 2012). The intrafamilial coexistence of SMA and ALS, therefore, occurs by chance.
Even though loss of SMN1 is not associated with ALS, CNVs in the SMN genes may modulate the clinical severity of ALS in addition to SMA. Multiple studies suggest that deletion of SMN2 leads to increased risk of the sporadic forms of amyotrophic lateral sclerosis (ALS) (Veldink et al., 2001, 2005; Kim et al., 2010; Corcia et al., 2012; Lee et al., 2012). Additionally, atypical SMN1 copy number—in other words, any number other than two—can affect the risk of ALS (Corcia et al., 2002b, 2006; Blauw et al., 2012; Wang et al., 2014b). Other studies, however, have shown no association between deletion of either SMN1 or SMN2 in ALS (Jackson et al., 1996; Moulard et al., 1998; Parboosingh et al., 1999; Crawford and Skolasky, 2002; Gamez et al., 2002). The discrepant results from these studies may be due, in part, to different assays used to assess SMN1 and SMN2 CNVs as some reports using quantitative PCR while others used MLPA or RFLP.
SMN and some ALS-associated proteins are involved in common biochemical pathways. Both familial and sporadic ALS have been linked to mutations in fused in sarcoma (FUS) (Kwiatkowski et al., 2009; Vance et al., 2009) (OMIM #608030) as well as in TAR DNA binding protein-43 kDa (TDP-43) (Kabashi et al., 2008; Sreedharan et al., 2008) (OMIM #612069). Both FUS and TDP-43 colocalize with SMN in subnuclear gems and ALS-associated mutations in FUS and TDP-43 reduce gem localization of SMN (Shan et al., 2010; Yamazaki et al., 2012; Gerbino et al., 2013; Groen et al., 2013; Ishihara et al., 2013; Sun et al., 2015). Gem localization of SMN, however, is not altered in other forms of sporadic ALS (Kariya et al., 2014). These mutant proteins also disrupt the SMN-mediated assembly of the splicing machinery by disrupting the interaction between SMN and U1-snRNPs (small nuclear ribonucleoprotein particles; Gerbino et al., 2013; Tsuiji et al., 2013; Sun et al., 2015; Yu et al., 2015). Additionally, ALS-associated FUS mutations disrupt the localization of SMN to axons (Groen et al., 2013). The SMN function, therefore, may be disrupted in certain forms of ALS.
Ectopic overexpression of SMN protects NSC34 motor neuron-like cells from cell death induced by ALS-associated mutant superoxide dismutase 1 (SOD1) (OMIM #105400) (Zou et al., 2007). The SOD1(G93A) transgenic mouse model for ALS that also harbors a knockout of 1 mSmn allele (SOD1(G93A)+∕−;mSmn+∕−) exhibits a more severe ALS phenotype than SOD1(G93A) ALS mice (SOD1(G93A)+∕−;mSmn+∕+) (Turner et al., 2009). Furthermore, ectopic overexpression of SMN in neurons and glia improves motor function of and delays motor neuron loss in SOD1(G93A) ALS mice (Turner et al., 2014). Strong transgenic overexpression of SMN2—in other words, eight copies of SMN2—delayed disease onset in the SOD1(G86R) mouse model for ALS (Kariya et al., 2012). Thesestudies suggest that increasing SMN expression may modulate disease severity in ALS. It will be interesting to determine the effect of SMN2 overexpression on disease severity in FUS- and TDP-43-associated ALS.
SMN1 and SMN2 CNVs in PMA
Progressive muscular atrophy (PMA) is an adult-onset motor neuron disease characterized by loss of LMNs (Rowland, 2010; Liewluck and Saperstein, 2015). It is a rare and sporadic disorder that is clinically distinct from ALS even though subclinical involvement of UMNs has been observed in many PMA patients. Those PMA patients exhibiting a more severe clinical presentation tend to harbor higher SMN1 copy numbers (Kuzma-Kozakiewicz et al., 2013). No relationship between SMN2 copy number and disease severity was noted in these PMA patients. Moulard et al. (1998) noted that the frequency of SMN2 deletion was higher in a small group of patients with sporadic LMN disease.
Conclusions
CNVs in the SMN genes can modulate disease severity in SMA as well as in other motor neurons. It is well-established that SMN2 copy number is inversely correlated with disease severity in SMA. Because of this relationship, SMN2 is a primary target for the development of therapeutics for SMA (Arnold and Burghes, 2013; Cherry et al., 2014). Numerous approaches including promoter activation, increased inclusion of exon 7 and protein stabilization are currently being developed to increase SMN2 expression. With respect to other motor neuron diseases, it is presently unclear whether increasing SMN1 or SMN2 expression would be beneficial or detrimental. On one hand, increasing SMN expression provides neuroprotective benefit to cell culture and transgenic mouse models for ALS; however, some genetic studies suggest that duplication of SMN1 increases the risk of sporadic ALS. Future studies will assess the relationship between SMN1 and SMN2 CNVs and disease risk and progression in ALS and PMA as well as in other disorders affecting motor neurons.
SMN2 copy number is becoming an inclusion criterion for many clinical trials for SMA. Additionally, SMN2 copy number can be used to help guide the type of care SMA patients will receive. It is, therefore, essential to be able to accurately and reliably measure SMN2 CNVs in SMA patient samples, especially for those individuals harboring more than three copies of SMN2. Newly developed technologies like dPCR offer a means to accurately determine SMN2 copy number over a wider range.
Statements
Author contributions
The author confirms being the sole contributor of this work and approved it for publication.
Acknowledgments
I would like to thank the members of the Motor Neuron Diseases Research Laboratory for their input. This review was supported by the Nemours Foundation and an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health (P20GM103464).
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- ALS
amyotrophic lateral sclerosis
- CNV
copy number variation
- dPCR
digital polymerase chain reaction
- FUS
fused in sarcoma
- GTF2H2
general transcription factor IIH
- LMN
lower motor neuron
- MLPA
multiple ligation-dependent probe amplification
- NAIP
neuronal apoptosis inhibitory protein
- OMIM
Online Mendelian Inheritance in Man
- PCR-RFLP
polymerase chain reaction-restriction fragment length polymorphism
- PMA
progressive muscular atrophy
- SERF1A
small EDRK-rich factor 1A
- SMA
spinal muscular atrophy
- SMNΔ7
survival motor neuron lacking exon 7
- SMN1
survival motor neuron 1
- SMN2
survival motor neuron 2
- snRNP
small nuclear ribonucleoprotein particle
- SOD1
superoxide dismutase 1
- TDP-43
TAR DNA binding protein-43kDa
- UMN
upper motor neuron.
Abbreviations
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Summary
Keywords
spinal muscular atrophy, amyotrophic lateral sclerosis, progressive muscular atrophy, neurodegenerative disease, copy number variation, SMN1, SMN2
Citation
Butchbach MER (2016) Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Front. Mol. Biosci. 3:7. doi: 10.3389/fmolb.2016.00007
Received
14 December 2015
Accepted
25 February 2016
Published
10 March 2016
Volume
3 - 2016
Edited by
Megha Agrawal, University of Arkansas at Little Rock, USA
Reviewed by
Alessandro Vercelli, University of Torino, Italy; Michal Mielcarek, Imperial College London, UK
Updates
Copyright
© 2016 Butchbach.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Matthew E. R. Butchbach butchbach@nemoursresearch.org
This article was submitted to Molecular Diagnostics, a section of the journal Frontiers in Molecular Biosciences
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