Alternative titles; symbols
HGNC Approved Gene Symbol: SMN2
Cytogenetic location: 5q13.2 Genomic coordinates (GRCh38) : 5:70,049,523-70,090,528 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q13.2 | {Spinal muscular atrophy, type III, modifier of} | 253400 | Autosomal recessive | 3 |
The SMN1 (600354) and SMN2 genes lie within the telomeric and centromeric halves, respectively, of a large, inverted duplication on chromosome 5q13. These genes share more than 99% nucleotide identity, and both are capable of encoding a 294-amino acid RNA-binding protein, SMN, that is required for efficient assembly of small nuclear ribonucleoprotein (snRNP) complexes. Homozygous loss of the SMN1 gene causes spinal muscular atrophy (SMA; 253300). Absence of SMN1 is partially compensated for by SMN2, which produces enough SMN protein to allow for relatively normal development in cell types other than motor neurons. However, SMN2 cannot fully compensate for loss of SMN1 because, although SMN2 is transcribed at a level comparable to that of SMN1, a large majority of SMN2 transcripts lack exon 7, resulting in production of a truncated, less stable SMN protein (Lefebvre et al., 1995; Kashima et al., 2007).
Lefebvre et al. (1995) described an inverted duplication of a 500-kb element in normal chromosome 5q13, which contains the gene for spinal muscular atrophy. Within the telomeric region, they identified the SMN1 gene. A highly homologous gene, referred to as C-BCD541 and also known as SMNC or SMN2, was present in the duplicated centromeric element in 95% of controls. PCR amplification and sequence analysis revealed 5 nucleotide discrepancies between the centromeric and telomeric SMN genes, 2 of which occur in exons 7 and 8. The centromeric SMN gene undergoes alternative splicing of exon 7, resulting in a truncated mRNA transcript lacking exon 7 and a putative protein with a different C-terminal end.
Using a panel of anti-SMN antibodies, Coovert et al. (1997) demonstrated that the SMN protein is expressed from both the SMN1 and SMN2 genes.
Burglen et al. (1996) determined that the SMN gene has 9 exons and spans approximately 20 kb. Burglen et al. (1996) referred to exon 2 as exons 2a and 2b.
Boda et al. (2004) determined that the first 4.6 kb of the SMN1 and SMN2 promoters are identical. The promoters contain 12 SP1 (189906), 8 AP1 (see 165160), 3 AP2 (107580), 6 HNF3 (see 602294), 24 Zeste (see 601674), and 4 RXR-beta (180246) sites. There are no RE1 elements. Boda et al. (2004) transfected primary cultures of mouse embryonic spinal cord and fibroblasts with constructs containing 1.8, 3.2, or 4.6 kb of the promoter region fused to a reporter gene. Expression of the 1.8- and 3.2-kb constructs was stronger in spinal cord than in fibroblast cultures; the 4.6-kb construct gave 5-fold higher expression in neurons than in fibroblasts, with expression in fibroblasts lower than that achieved with the 3.2-kb construct. Boda et al. (2004) concluded that these results suggest the presence of an enhancer element between 1.8 and 3.2 kb upstream from the transcriptional start site of the SMN genes that functions in both culture types, and a silencer between 3.2 and 4.6 kb that is active only in fibroblast cultures.
Lefebvre et al. (1995) determined that the SMN2 gene lies within the centromeric half of a large inverted duplication on chromosome 5q13. The SMN1 gene lies in the telomeric half of the duplication.
Monani et al. (1999) sequenced 3 genomic clones over 32 kb in length, which spanned both the SMN1 and SMN2 genes. Of 35 sequence differences noted between SMN1 and SMN2, only 3 were located in either exon 7 or intron 7. Of note was a translationally silent 840C-T transition at position +6 in exon 7, which affects splicing. Using minigene constructs, the authors found that the presence of cytosine at position +6 in exon 7 produced a normal splicing pattern retaining exon 7, whereas thymine in this position resulted in the absence of exon 7 in the majority of the transcripts. Since the majority of human SMN2 transcripts lack exon 7, the authors hypothesized that the 5-prime portion of exon 7 in SMN1 contains an exonic splice enhancer (ESE), and that low levels of full-length SMN transcript are responsible for the SMA phenotype.
Andreassi et al. (2001) screened a library of compounds and found that aclarubicin increased the retention of exon 7 into the SMN2 transcript from the endogenous gene in type I SMA fibroblasts, as well as from an SMN2 minigene in a motor neuron cell line. In type I fibroblasts, treatment resulted in an increase in SMN protein and gems to normal levels. The authors demonstrated the utility of high-throughput screens in detecting compounds that affect the splicing pattern of a gene, and suggested that alteration of splicing patterns may represent a feasible approach to modification of gene expression in disease treatment.
Using in vivo splicing assays, Hofmann and Wirth (2002) identified the protein hnRNPG (300199) and its paralog RBM (400006) as 2 novel splicing factors that promote the inclusion of SMN2 exon 7. Both hnRNPG and RBM nonspecifically bind RNA, but directly and specifically bind Htra2-beta1, an SR-like splicing factor which stimulates inclusion of exon 7 through a direct interaction with SMN2 exon 7 pre-mRNA. Using deletion mutants of hnRNPG, the authors demonstrated a specific protein-protein interaction of hnRNPG with Htra2-beta1 which mediates the inclusion of SMN2 exon 7 rather than the nonspecific interaction of hnRNPG with SMN pre-mRNA. These trans-acting splicing factors were also effective on endogenous SMN2 transcripts and increased the endogenous SMN protein level. The authors presented a model of how exon 7 mRNA processing may be regulated by these splicing factors.
Kashima and Manley (2003) showed that the exonic splicing silencer in SMN2 functions as a binding site for a known repressor protein, HNRNPA1 (164017), which binds to SMN2 but not SMN1 exon 7 RNA. By using small interfering RNAs (siRNAs) to reduce HNRNPA1 protein levels in living cells, Kashima and Manley (2003) demonstrated efficient SMN2 exon 7 splicing. The findings not only defined a new mechanism underlying the inefficient splicing of SMN2 exon 7 but also illustrated more generally the remarkable sensitivity and precision that characterizes control of mRNA splicing. The work also made it possible to consider therapeutic approaches to spinal muscular atrophy that involved decreasing HNRNPA1 RNA binding to or function on SMN2 exon 7.
Helmken et al. (2003) stated that sibs with identical 5q13 homologs and homozygous absence of SMN1 can have variable phenotypes, suggesting that the spinal muscular atrophy phenotype is modified by other factors, which function either on the transcriptional level, to produce more full-length SMN (FL-SMN) transcripts, or on the translational level, to increase the amount of SMN2 protein. By analyzing 9 SMA discordant families, Helmken et al. (2003) demonstrated that in all families unaffected sibs produced significantly higher amounts of SMN, SMN-interacting protein-1 (SIP1; 602595), GEMIN3 (606168), ZPR1 (603901), and hnRNPQ protein in lymphoblastoid cell lines, but not in primary fibroblasts, compared with their affected sibs. The results suggested that the modifying factor or factors act on the SMN gene to influence SMN protein levels, thus modifying the SMA phenotype, and not through an independent pathway. In addition, the observed coregulations appeared to be tissue-specific. SMN significantly coregulated its interacting partners, including its own splicing factor, HTRA2-beta-1 (see 606441), due to an indirect feedback mechanism. Thus, Helmken et al. (2003) showed that reduction of the SMN protein has a significant impact on the expression level of a splicing factor.
Brichta et al. (2003) showed that in fibroblast cultures derived from SMA patients treated with therapeutic doses of valproic acid, the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. This upregulation of SMN was most likely attributable to increased levels of HTRA2-beta-1 as well as to SMN gene transcription activation. Valproic acid also increased SMN protein levels through transcription activation in organotypic hippocampal rat brain slices. Additionally, valproic acid increased the expression of other serine-arginine family proteins, which may have important implications for other disorders affected by alternative splicing.
Grzeschik et al. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription.
Kernochan et al. (2005) investigated the levels of acetylated H3 and H4 histones and histone deacetylases (HDACs) associated with different regions of the human and mouse SMN genes in both cultured cells and tissues. The SMN gene had a reproducible pattern of histone acetylation that was largely conserved among different tissues and species. A limited region of the promoter surrounding the transcriptional start site had relatively high levels of histone acetylation. After HDAC inhibitor treatment, acetylated histone levels increased, particularly at upstream regions, correlating with a 2-fold increase in promoter activity. During development in mouse tissues, histone acetylation levels decreased and associated HDAC2 (605164) levels increased at the region closest to the transcriptional start site, correlating with a 40 to 60% decrease in SMN transcript and protein levels. Kernochan et al. (2005) suggested that histone acetylation may modulate SMN gene expression.
Skipping of SMN2 exon 7 had been attributed to either the loss of an SF2/ASF-dependent exonic splicing enhancer or the creation of an hnRNP A/B-dependent exonic splicing silencer, as a result of the C-to-T transition. Cartegni et al. (2006) reported the extensive testing of the enhancer-loss and silencer-gain models by mutagenesis, RNA interference, overexpression, RNA splicing, and RNA-protein interaction experiments. The results supported the enhancer-loss model but also demonstrated that hnRNP A/B proteins antagonize SF2/ASF-dependent ESE activity and promote exon 7 skipping by a mechanism that is independent of the C-to-T transition and is, therefore, common to both SMN1 and SMN2. The findings explained the basis of defective SMN2 splicing, illustrated the fine balance between positive and negative determinants of exon identity and alternative splicing, and underscored the importance of antagonistic splicing factors and exonic elements in a disease context.
Kashima et al. (2007) showed that the 840C-T transition in SMN2 created a high-affinity HNRNPA1-binding site. Depletion of HNRNPA1 in HeLa cells restored exon 7 inclusion, indicating that splicing of exon 7 in SMN2 is repressed by an HNRNPA1-dependent exonic splicing silencer.
Kashima et al. (2007) identified a novel single nucleotide difference between SMN1 and SMN2, an A-to-G change at position +100 within intron 7 of SMN2, which creates a second high-affinity HNRNPA1-binding site specific to SMN2. Base substitutions that disrupted this site in SMN2 restored exon 7 inclusion in vivo and prevented HNRNPA1 binding in vitro. Kashima et al. (2007) proposed that interactions between HNRNPA1 molecules bound to the exonic and intronic sites cooperate to exclude exon 7 in SMN2.
Angelozzi et al. (2008) found that salbutamol increased full-length SMN2 mRNA transcript levels in fibroblasts derived from patients with SMA. The maximum increase (over 200%) was observed after 30 to 60 minutes. This rapid rise correlated with decreased levels of SMN2 mRNA with deletion of exon 7. Salbutamol treatment also resulted in increased SMN protein levels and nuclear gems.
Using SMN minigenes, Gladman and Chandler (2009) identified 2 elements within intron 7 of the SMN genes that influenced exon 7 splicing in a cell type-independent manner.
Using in vitro splicing assays, minigenes, and knockdown and overexpression studies with human constructs and cells, Jodelka et al. (2010) showed that total SMN protein content and the relative abundance of individual snRNPs determined inclusion or skipping of SMN2 exon 7. Exon 7 was not included in SMN2 mRNAs in the absence of SMN protein. Exon 7 inclusion was highly sensitive to the level of U1 snRNP. Jodelka et al. (2010) noted that U1 snRNP recognizes the 5-prime splice site of pre-mRNAs through direct basepairing, and they found that the 5-prime splice site of SMN2 exon 7 was a critical determinant of exon inclusion. Jodelka et al. (2010) concluded that SMN protein controls its own expression via positive-feedback regulation of alternative SMN2 pre-mRNA splicing and that reduced SMN protein content in SMA has a deleterious effect on expression of the full-length protein via SMN2 mRNA.
Spinal Muscular Atrophy
Hahnen et al. (1996) reported molecular analysis of 42 SMA patients who carried homozygous deletions of exon 7 but not of exon 8 in the telomeric copy of the SMN gene (SMN1). Additional homozygous deletions of exon 8 in the centromeric copy of SMN (SMN2) were found in 2 of the patients. By a simple PCR test, they demonstrated the existence of hybrid SMN genes, i.e., genes composed of both the centromeric SMN2 and the telomeric SMN1. They reported a high frequency of hybrid SMN genes in SMA patients with Czech or Polish background. Hahnen et al. (1996) identified a single haplotype for half of the hybrid genes analyzed, suggesting that in these cases the SMA chromosomes shared a common origin.
Schwartz et al. (1997) used solid-phase minisequencing to determine the ratio between the number of telomeric and centromeric copies of the SMN gene in affected and unaffected members of 30 SMA families. Six predominant haplotypes were identified, 3 for normal chromosomes and 3 for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of SMN2. They found patients homozygous for a deletion of SMN1 and with only one copy of SMN2, but found none deleted for all copies of SMN2. Several asymptomatic carriers of SMA with only a single copy of SMN1 and no copy of SMN2 were identified. Schwartz et al. (1997) could not confirm the hypothesis that the presence of more copies of SMN2 is correlated with a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of SMN2 were found to differ significantly between normal and SMA chromosomes. This distribution could be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes.
Srivastava et al. (2001) reported a 5-year-old boy with childhood-onset SMA who had a homozygous deletion of SMN2. He had wasting, weakness, and hyporeflexia, predominantly in the distal muscles. The affected muscles showed chronic neurogenic changes on electromyography. There was no sensory involvement. A nerve conduction study showed near-normal conduction velocity with reduction in the amplitude of the compound muscle action potential. The SMN2 deletion was demonstrated by studies of exons 7 and 8 of the SMN genes. Base sequencing and densitometric analysis of the critical exon 7 region did not show any microdeletion or duplication of SMN1, but confirmed the deletion of SMN2. Srivastava et al. (2001) concluded that deletion of SMN2 can also result in the SMA phenotype.
Feldkotter et al. (2002) developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, Feldkotter et al. (2002) calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA.
Ogino et al. (2004) analyzed all 'available and reliable' data to calculate allele/haplotype frequencies and new mutation rates in the SMN region. The authors stated that their data provided the basis for the most accurate genetic risk calculations as well as evidence that nucleotide position 840 constitutes a mutation hotspot. Ogino et al. (2004) suggested that there is selection of the single-copy SMN1-SMN2 haplotype and that rare chromosomes with 3 copies of SMN1 exist.
Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 (253400) or SMA4 (271150) who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis.
Hauke et al. (2009) demonstrated that SMN2 is subject to gene silencing by DNA methylation. SMN2 contains 4 CpG islands which present highly conserved methylation patterns and little interindividual variation in SMN1-deleted SMA patients. The comprehensive analysis of SMN2 methylation in patients suffering from severe versus mild SMA carrying identical SMN2 copy numbers revealed a correlation of CpG methylation at the positions -290 and -296 with disease severity and the activity of the first transcriptional start site of SMN2 at position -296. The methyl-CpG-binding protein-2 (MECP2; 300005), a transcriptional repressor, bound to the critical SMN2 promoter region in a methylation-dependent manner. The authors identified histone deacetylase (HDAC) inhibitors (including vorinostat and romidepsin) that were able to bypass SMN2 gene silencing by DNA methylation, while others (such as valproic acid and phenylbutyrate) did not, due to HDAC isoenzyme specificities. The authors concluded that DNA methylation is functionally important regarding SMA disease progression, and pharmacologic SMN2 gene activation might have implications for future SMA therapy regimens.
Amyotrophic Lateral Sclerosis
Moulard et al. (1998) found homozygous deletions of SMN2 in 36% of individuals with sporadic adult-onset lower motor neuron disease (LMND), but in only 6.2% of individuals with sporadic amyotrophic lateral sclerosis (ALS; 105400) and 1.5% of individuals with familial ALS. The authors argued that SMN2, but not SMN1, deletions are a susceptibility factor for LMND, a disorder distinguishable from ALS by the absence of upper motor neuron signs. LMND patients with SMN2 deletions differed from those patients without such deletions by earlier age of onset (40 vs 56 years), more rapid disease progression (25 vs 36 months to death), and a lower preponderance of males (M:F ratio of 1.5 vs 2.5).
Among 124 ALS patients, Gamez et al. (2002) found no association between homozygous deletion of SMN2 and disease onset, respiratory decline, or survival. A homozygous SMN2 deletion was identified in 11 (8.8%) patients and 20 (10%) of 200 control individuals. Corcia et al. (2002) found no difference in SMN2 gene copies among 167 ALS patients and 167 controls. Homozygous deletion of the SMN2 gene was found in 9 and 10% of patients and controls, respectively. Among 600 patients with sporadic ALS, Corcia et al. (2006) found no disease association with SMN2 copy number.
Crawford and Skolasky (2002) briefly reviewed several reported associations of SMN to ALS and concluded that the findings likely represented nonsignificant or borderline significant fluctuations. Corcia et al. (2002) responded that although they still supported a role for the SMN2 gene in LMND (Moulard et al., 1998), the evidence of an association between homozygous SMN2 deletion and ALS was less convincing.
Rochette et al. (2001) used a number of approaches to probe the evolutionary history of the SMN1 and SMN2 genes and showed that SMN gene duplication and the appearance of SMN2 occurred at very distinct evolutionary times. Molecular fossil and molecular clock data suggested that this duplication may have occurred as recently as 3 million years ago in that the position and repetitive elements are identical for both human SMN genes and overall sequence divergence ranges from 0.15 to 0.34%. However, these approaches ignored the possibility of sequence homogenization by means of gene conversion. Consequently, Rochette et al. (2001) used quantitative polymerase chain reaction and analysis of allelic variants to provide physical evidence for or against SMN gene duplication in the chimpanzee, mankind's closest relative. These studies revealed that chimpanzees have 2 to 7 copies of the SMN gene per diploid genome; however, the 2 nucleotides diagnostic for exons 7-8 and the SMNdel7 mRNA product of the SMN2 gene are absent in nonhuman primates. In contrast, the SMN2 gene has been detected in all extant human populations studied to date, including representatives from Europe, the Central African Republic, and the Congo. These data provided conclusive evidence that SMN gene duplication occurred more than 5 million years ago, before the separation of human and chimpanzee lineages, but that SMN2 appeared for the first time in Homo sapiens.
Le et al. (2005) created transgenic mice expressing SMN2 lacking exon 7 (SMN-delta-7) and crossed them onto a severe SMA background. Expression of SMN-delta-7 appeared to extend survival of SMA mice from 5 to 13 days. Unlike mice with selective deletion of SMN exon 7 in muscle, mice with a small amount of full-length SMN (FL-SMN) did not show a dystrophic phenotype. The authors suggested that low levels of FL-SMN (as found in SMA patients) and absence of FL-SMN in muscle tissue may have different effects, and raised the question of the importance of high SMN levels in muscle in the presentation of SMA. SMN and SMN-delta-7 can associate with each other; Le et al. (2005) suggested that this association may stabilize SMN-delta-7 protein turnover and ameliorate the SMA phenotype by increasing the amount of oligomeric SMN.
In SMA-like mouse embryonic fibroblasts and human SMN2-transfected motor neuron cells, Ting et al. (2007) found that sodium vanadate, trichostatin A, and aclarubicin effectively enhanced SMN2 expression by inducing Stat5 (601511) activation. This resulted in enhanced SMN2 promoter activity with an increase in both full-length and deletion exon 7 SMN transcripts in human cells with SMN2. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation, but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. Constitutive expression of the activated Stat5 mutant Stat5A1*6 profoundly increased the number of nuclear gems in SMA patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects.
Workman et al. (2009) showed that SMN(A111G), an allele capable of snRNP assembly (A111G; 600354.0015), can rescue mice that lacked Smn and contained either 1 or 2 copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) could not rescue Smn-null mice without SMN2, suggesting that both SMN(A111G) and SMN from SMN2 may undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) had substantial snRNP assembly activity. The SMN(A2G) (A2G; 600354.0002) and SMN(A111G) alleles in vivo did not complement each other, leading to the possibility that these mutations could affect the same function.
Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV; see 253400) known as Kugelberg-Welander disease.
Through chemical screening and optimization, Naryshkin et al. (2014) identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 mRNA with high selectivity. Administration of these compounds to delta-7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice.
In a 42-year-old woman with a mild form of SMA type III (253400), despite a homozygous absence of SMN1 exon 7 (600354), Prior et al. (2009) identified a homozygous 859G-C transversion in exon 7 of the SMN2 gene, resulting in a gly287-to-arg (G287R) substitution. In vitro functional expression studies showed that the change resulted in the creation of an exonic splicing enhancer element and increased the amount of full-length SMN2 transcripts compared to wildtype. The SMN1 genotype (0 SMN1, 0 SNM2) predicted a more severe disorder (SMA1; 253300), but the SMN2 variant increased SMN2 transcripts, resulting in a less severe phenotype. The same 859G-C transversion was identified in heterozygosity in 2 additional unrelated patients with mild forms of SMA, who were predicted to have a more severe form of the disorder from their genotypes (0 SMN1/1 SMN2 and 0 SMN1, 2 SMN2).
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