Human Molecular Genetics, 2000, Vol. 9, No. 16 2451-2457
© 2000 Oxford University Press
Animal models of spinal muscular atrophy
1Department of Neurology, Means Hall, 1654 Upham Drive and 2Department of Molecular and Cellular Biochemistry, Hamilton Hall, 1645 Neil Avenue, The Ohio State University, Columbus, OH 43210, USA
Received 26 June 2000; Revised and Accepted 14 July 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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Proximal spinal muscular atrophy (SMA) is the second most common autosomal recessive inherited disorder in humans. It is the most common genetic cause of infant mortality. As yet, there is no cure for this neuromuscular disorder which affects the lower motor neurons and proximal muscles of the limbs and trunk. In the last decade, significant advances have been made in understanding this disease, from linkage analysis to isolating the defective gene and identifying its protein product. This review summarizes the most recent advance in SMA research: the development of animal models of the disease, in particular mouse models of SMA. The SMA mice that we describe here present with symptoms similar to those seen in SMA patients. They promise to further the understanding of the molecular basis of this disease and demonstrate the feasibility of using the intact SMN2 gene, found in all SMA patients, as a means of treating this disorder.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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The spinal muscular atrophies (SMAs) are a group of disorders characterized by degeneration of the spinal motor neurons (1). Dominant, recessive and X-linked forms of the SMAs have been described. The precise molecular mutations responsible for the SMAs have only been described for the X-linked and the recessive forms (2–7). The X-linked form is caused by a CAG (glutamine) expansion in the androgen receptor (8). In this review, we will concentrate on the proximal autosomal recessive forms of SMA. The proximal SMAs have an incidence of
1 in 10 000 and a carrier frequency of 1 in 50 (9–11). They can be divided into three groups based on age at onset and clinical course (12,13). Type I SMA is the most severe, with onset occurring by 6 months of age and death by 2 years. Type II patients have an intermediate severity, with onset before the age of 18 months and patients never gaining the ability to walk. Type III SMA is the mildest form, with onset after the age of 18 months. Patients are able to stand and walk. The SMA gene was mapped by linkage analysis to 5q12 (14,15). This region of the genome contains numerous repeats and multiple copies of both markers and genes (3,16–21). In particular, the survival of motor neuron gene has two copies on a chromosome: a telomeric copy (SMN1) and a centromeric copy (SMN2). Loss of the SMN2 gene has no phenotypic effect, whereas loss of SMN1 results in SMA. In humans, the number of copies of SMN genes present can vary, and the SMA locus may contain zero, one or two copies of each gene. In a rare case, a patient was found to carry eight copies of SMN2 (22). The genes adjacent to SMN are also duplicated, but the nature of the duplication and the exact copy number of the various genes differ in different species.
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THE SMA DUPLICATED REGION IN MAN AND MOUSE |
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TOPABSTRACTINTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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Figure 1 shows the SMA critical region in man and mouse. As can be seen, the nature of the duplication is different. In mice, there are multiple copies of intact neuronal apoptosis inhibitory protein (NAIP) whereas humans carry only a single copy of the complete NAIP gene (23,24). SMN, on the other hand, is duplicated in humans; it exists as a single copy in mice (Smn) which is assumed to be the equivalent of human SMN1. As the copy number of these genes is polymorphic in humans, it is perhaps not surprising that the exact structure is not conserved in mice. Moreover, it indicates a highly dynamic and variable region which is prone to rearrangements.
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THE MOLECULAR GENETICS OF SMA |
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TOPABSTRACTINTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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All three forms of SMA are caused by mutations in the SMN1 gene which is usually lost by deletion or gene conversion. This results in 98% of SMA patients, regardless of phenotypic severity, having no detectable SMN1 gene. The remaining 2% of cases retain a copy of the SMN1 gene which has a small mutation of some type in it. All SMA patients retain at least one intact copy of the SMN2 gene. This implies that complete absence of the SMN genes in man, as in the mouse, is embryonic lethal (25). An obvious question that follows is why does the SMN2 gene not compensate for the loss of the SMN1 gene? The promoters of the two genes are equivalent, with some variation in activity due to polymorphisms within this region (26,27). Sequence analysis of the entire SMN1 and SMN2 genes shows that they are virtually identical, even within introns (28). The only variations that can be used to mark the SMN1 and SMN2 genes are differences lying between intron 6 and exon 8. These have been analyzed extensively using SMA patient samples with chimeric genes. Only a single nucleotide difference in exon 7 emerges as being able to distinguish SMN1 from SMN2. This single nucleotide difference, 6 bp inside exon 7, does not alter an encoded amino acid but does affect incorporation of the exon into the transcript (29). Additionally, an SMA patient has been identified who possesses an alteration in the splice donor site of exon 7, which alters its incorporation into the mRNA (29). Taken together, these data clearly indicate that the critical difference between SMN1 and SMN2 is the single nucleotide difference which causes alteration of the activity of an exon splice enhancer (ESE) in exon 7 such that SMN2 produces higher levels of transcript lacking exon 7. This splice enhancer currently is undergoing extensive analysis to determine the splice factors that bind it (30).
Figure 2 summarizes the effect of the C
T sequence change in exon 7 on SMN protein levels from the two genes. SMN2 produces mostly transcript lacking exon 7. This is translated into an unstable protein which is degraded rapidly. Thus, SMA patients produce reduced levels of SMN, although type II and III patients do produce more protein than type I patients (31,32). SMA is therefore caused by a deficiency of the SMN protein which affects motor neurons in particular.
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Since SMN2 does produce a certain amount of SMN protein, its copy number would be predicted to be important in determining phenotype. Comparison of SMN2 copy number in SMA patients with different severities indicates a strong correlation of copy number to phenotypic severity (11,33). In general, more copies of SMN2 genes are found in the milder SMA patients than in the severe SMA patients. Although the copy number of SMN2 does account for most of the phenotypic severity, it is not the only factor. Patients have been identified who are exceptions to the SMN2 copy number rule. Additionally, siblings having identical SMN2 copy number but markedly different clinical phenotypes have been described (34–39). DNA analysis of the sibs showed that they were also haploidentical for flanking markers and genes. This indicates the presence of modifier loci lying outside the SMA locus. These could either act directly by modifying the expression level of SMN or indirectly by compensating for the functional loss of the protein. The genes that flank the SMN1 locus, namely NAIP and SERF-1, have been suggested to act as phenotypic modifiers (20,40), but there is little evidence from patient analysis to indicate that this is the case. The availability of animal models of SMA will allow this question to be resolved.
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THE SMN PROTEIN AND ITS INTERACTING PARTNERS |
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TOPABSTRACTINTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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The 38 kDa SMN protein is found in both cytoplasm and nucleus of all tissues examined. The abundance of expression varies among the different tissues, with the greatest expression in the brain, spinal cord and muscle, and the lowest relative expression occurring in the lymphocytes and fibroblasts (31,32). In the nucleus, SMN is concentrated in aggregates called gemini of coiled bodies (gems), so named because gems are found in close association with the coiled bodies (41). Certain tissue types, for example cardiac and smooth muscle, do not have either coiled bodies or gems, indicating that nuclear bodies may be storage sites for reserves of essential proteins and snRNPs (42). SMA patients have reduced numbers of gems. This is particularly striking in tissue from type I SMA patients. The SMN protein has been shown to self-associate via its C-terminal domain (43) and more recently through its N-terminus (44). Missense mutations in SMN disrupt this association. However, conclusions about SMN function and SMA from biochemical assays (45) using these missense mutations should be interpreted with caution. This is because the alleles with the mutations always exist on an SMN2 background in patients. The assays, on the other hand, use the missense mutations without SMN2. This would result in the formation of mutant homodimers of the protein rather than heterodimers comprising normal protein from SMN2. In addition to self-associating, SMN forms a complex with a series of proteins: the Sm proteins, SIP-1 (gemin 2), gemin 3 and gemin 4 (46–50). The complex has been shown to function in snRNP biogenesis, cycling between the cytoplasm and nucleus. In the nucleus, it is involved in pre-mRNA splicing. Recently, SMN has been shown to bind the Sm proteins via its tudor domain. A patient missense mutation in this domain disrupts Sm binding but not oligomerization (51). Other proteins reported to interact with SMN include profilins and transcription factors E2 and FUSE (52,53). Profilins (PFN-1 and -2) bind to a proline-rich region in SMN. PFN-2 is neuron specific and functions in the depolymerization of actin filaments, indicating a possible role for the SMN–PFN-2 complex in neural transport (54). SMN has also been reported to interact with the anti-apoptotic protein Bcl-2 (55). The interaction has never been reproduced in independent laboratories and this reported interaction remains dubious (56).
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ANIMAL MODELS OF SMA INVOLVING THE SMN GENES |
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TOPABSTRACTINTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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The interactions between the various proteins described above and SMN have provided us with important leads to the function of this protein. However, a key question remains: why is SMA a motor neuron disease? Three proposals have been put forward. First, SMN plays a similar role in all cells; however, motor neurons are uniquely sensitive to low levels of the protein. Secondly, SMN has a unique function in motor neurons; and, thirdly, low SMN levels in the motor neurons cause inappropriate splicing of one or more message critical to the survival of these cells. We feel that the animal models of SMA described below will be critical in answering this.
The identification of the murine homolog of the SMN gene (Smn) (57,58) made it possible to knock it out (25). Although the complete knockout did not result in a useful mouse model of SMA, it provided definite evidence that SMN is an essential gene. Complete lack of the SMN protein is embryonic lethal. This is not surprising given the fact that all SMA patients carry at least one intact SMN2 gene and that absence of both SMN genes in humans has never been reported. Two approaches were taken to overcome the embryonic lethality in Smn–/– mice. Frugier et al. (59) made a conditional knockout of the murine Smn gene using the Cre–LoxP system in which they targeted exon 7. Mice carrying exon 7 flanked by LoxP sites were crossed with mice also transgenic for Cre recombinase. To knock out exon 7 in the motor neurons, the recombinase was expressed under the control of the NSE (neuron-specific enolase) promoter. Approximately 25% of the offspring from this cross lack full-length (FL) SMN in neuronal cells and display many of the symptoms seen in SMA patients. This report clearly shows the importance of SMN transcript containing exon 7 in SMA. However, certain problems remain. The most important of these stems from the fact that SMA is caused by uniformly low levels of FL-SMN in motor neurons, whereas the approach of Frugier et al. (59) results in a continual depletion of FL-SMN in neuronal cells when the NSE promoter is turned on. Ultimately, a certain proportion of motor neurons are completely lacking in FL-SMN; others continue to produce normal levels of the protein. This is due partially to the incomplete specificity of the NSE promoter for motor neurons and its lack of activity in a certain proportion of neuronal cells which we assume continue to produce normal levels of FL-SMN.
The report of our group (60) and that of Hsieh-Li et al. (61) describe a different approach. Both recognized that SMA patients always carry one or more SMN2 genes and used this gene to rescue the embryonic lethality in Smn–/– mice. Although there are minor differences between the two reports, the essential observations are the same. SMN2 is able to rescue the embryonic lethal phenotype of Smn–/– mice and an increase in the copy number of the gene results in a milder phenotype. Data from our group have shown that mice with a single SMN2 gene are stillborn or die within 12 h of birth. Mice possessing two copies of SMN2 survive to 6 days of age. Hsieh-Li et al. (61) report severe SMA mice surviving to 10 days of age. They also report seeing mice with all three forms of SMA in the same litter. We have never seen this nor has it been reported in the human patient population (T. Crawford, personal communication). The difference in survival time of the severe SMA mice reported by our groups could be due to strain differences between our transgenic mice (FVB and C57BL/6) and theirs (FVB, 129/SvJ and C57BL/6). Alternatively, it could be due to the way the knockouts were constructed. Whereas ours is a null allele, deleted for exon 2, that results in embryonic lethality at the eight-cell stage, Hsieh-Li et al. knocked out exon 7. Embryos which are homozygous for this allele survive until embryonic day 3.5. A third explanation is the difference in size of the transgenes and the possibility that the bacterial artificial chromosome (BAC) clone that Hsieh-Li et al. used contains modifier loci, e.g. SERF-1. However, we feel that this is unlikely from SMA patient data and the fact that SERF-1 and SERF-2 are identical. Nevertheless, the severe SMA mice from both our groups have a remarkably similar phenotype to that seen in severe type I SMA infants. They produce low levels of SMN protein and immunohistochemical techniques do not detect any gems in the spinal motor neurons (Fig. 3). Further, it is clear from western blot data that SMN is developmentally regulated. This is corroborated in studies of Smn+/– mice in which there is a significant decrease in SMN and loss of motor neurons with age (62). Finally, data from our group have shown that motor neuron loss is a late onset phenomenon and occurs after birth in SMA mice. This observation, as well as the possibility of turning on the SMN2 gene to compensate for the absence of SMN1 in SMA patients, makes the SMN2 transgenic mice invaluable in identifying appropriate therapeutic drugs for the treatment of the disease. There is little doubt of the feasibility of this as we have shown that the level of expression from eight copies of the SMN2 gene on the Smn–/– knockout background completely corrects the SMA phenotype. The eight-copy SMN2;Smn–/– mice have shown no overt SMA phenotype or muscle weakness and are currently 18 months of age.
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ANIMAL MODELS OF SMA INVOLVING OTHER LOCI |
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TOPABSTRACTINTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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The animal models described above were developed recently. However, the SMAs and their characteristic features were recognized decades ago. Mutations in numerous genes in both mouse and man give rise to pathophysiologies similar to those seen in SMA. It is therefore not surprising that some well-known mouse mutants have been touted as animal models of SMA (63) (Table 1). These include the wobbler, muscle deficient (MDF) and progressive motor neuronopathy (pmn) mutants in mice (64–66) and the hereditary canine spinal muscular atrophy (HCSMA) model in dogs (67). In addition, there have been numerous other reports of animal models of SMA (reviewed in ref. 68). However, although these models do present with pathologies similar to SMA, none of them are a result of mutations in the SMN gene. It is important to keep this in mind both from the standpoint of gaining a better understanding of the SMA disease process and from the perspective of therapeutic intervention. Many of the remaining questions about SMA may be addressed using these animal models; however, we feel that it is extremely important to confirm them in the most accurate models of this disease, i.e. those involving the SMN gene(s). In addition, it might perhaps be prudent to re-classify ‘animal models of SMA’ involving other loci simply as animal models of motor neuron disease (MND).
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Finally, it is worth noting that the SMN gene has remained highly conserved during evolution (6). Yeast (Schizosaccharomyces pombe), nematode (Caenorhabditis elegans) and Drosophila homologs of the gene have been identified (69–71). Although these organisms lack the complex nervous system of vertebrates and may not be the most suitable models to study the role of SMN in motor neurons, they lend themselves easily to genetic manipulation and have already provided important clues to the function of SMN in living organisms (69–71).
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FURTHER USES OF THE ANIMAL MODELS OF SMA AND FUTURE DIRECTIONS |
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TOPABSTRACTINTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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The recent development of the mouse models of SMA described in this review is clearly an important one. They have provided the most definite evidence, so far, of the importance of SMN exon 7, the role of SMN2 in the disease process and the ability of this gene, if needed, to completely rescue the SMA phenotype. The animal models have also provided us with clues to the timing of motor neuron loss. However, a number of questions remain. Why does SMA affect the motor neurons so selectively? Is SMA really a motor neuron disease or does the disease affect primarily the muscle, with motor neuron degeneration being a secondary effect? Does SMN play a unique role in these tissues? Is cell death, due to low SMN levels, apoptotic? Is it possible to tweak SMN2 into increasing its expression of FL-SMN? These are examples of just some of the questions that we feel can be answered using the mouse models. Two of these questions are already in the process of being answered. First, the tissue-specific expression of SMN in SMA mice is being used to determine the importance of this protein to certain cells and, secondly, high-throughput drug screens to identify compounds which will hyperexpress SMN2 are underway. These drugs will be tested in the SMN2 transgenic mice before proceeding to clinical trials. The SMA mice will also be important in determining and/or confirming important domains of the SMN protein. Missense mutations identified in SMA patients may be expressed in transgenic animals carrying or lacking an SMN2 copy. This is one way of determining whether mutant homodimers are functional or whether heterodimers involving low levels of SMN from SMN2 are required for functionality. Thus, it is clear that the animal models of SMA brings us one step closer to understanding more completely and eventually treating this devastating neuromuscular disease.
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ACKNOWLEDGEMENTS |
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We thank C. Andreassi and D. Wise for help with this manuscript. We are grateful to all the families affected one way or another by spinal muscular atrophy. Meeting and speaking to them makes researching this disease a very worthwhile endeavor. Research in this laboratory is supported by FSMA, MDA of America, the Madison, Preston and Matthew Funds and NIH grant NS38650 to A.H.M.B.
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FOOTNOTES |
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+ To whom correspondence should be addressed at: 363 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA. Tel: +1 614 688 4759; Fax: +1 614 292 4118; Email: burghes.1@osu.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONTHE SMA DUPLICATED REGION...THE MOLECULAR GENETICS OF...THE SMN PROTEIN AND...ANIMAL MODELS OF SMA...ANIMAL MODELS OF SMA...FURTHER USES OF THE...REFERENCES |
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