Human Molecular Genetics, 2000, Vol. 9, No. 3 333-339
© 2000 Oxford University Press
The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn–/– mice and results in a mouse with spinal muscular atrophy
Departments of 1Neurology, 2Pathology and 3Medical Biochemistry, College of Medicine and 4Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH 43210, USA, 5Department of Neurology, University of Würzburg, Josef-Schneider Strasse 11, D-97080 Würzburg, Germany and 6MRIC, Biochemistry Group, Northeast Wales Institute, Wrexham, UK
Received 2 December 1999; Revised and Accepted 13 December 1999.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans and in its most severe form causes death by the age of 2 years. It is caused by defects in the telomeric survival motor neuron gene (SMN1), but patients retain at least one copy of a highly homologous gene, centromeric SMN (SMN2). Mice possess only one survival motor neuron gene (Smn) whose loss is embryonic lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that express human SMN2 and mated these onto the null Smn–/– background. We show that Smn–/–;SMN2 mice carrying one or two copies of the transgene have normal numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5, and subsequently die. This closely resembles a severe type I SMA phenotype in humans and is the first report of an animal model of the disease. Eight copies of the transgene rescues this phenotype in the mice indicating that phenotypic severity can be modulated by SMN2 copy number. These results show that SMA is caused by insufficient SMN production by the SMN2 gene and that increased expression of the SMN2 gene may provide a strategy for treating SMA patients.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Proximal spinal muscular atrophy (SMA) is the most common inherited cause of childhood mortality with an incidence of 1 in 10 000 live births (1,2). It is an autosomal recessive disorder that is characterized by the destruction of the
motor neurons in the spinal cord. Based on the clinical severity and age at onset, the childhood SMAs have been divided into three types (3,4). Type I SMA is the most severe form with onset before 6 months and death occurring by the age of 2 years. Type II SMA is intermediate in severity with onset before 18 months of age and patients never gaining the ability to walk. Type III SMA is the mildest form of the disease with onset after 18 months. Type III SMA patients are able to walk. SMA is caused by mutations in the telomeric survival motor neuron gene (SMN1) but not the centromeric survival motor neuron gene (SMN2) (5–9). However, the SMN transcript is encoded by both genes and SMA patients do produce low levels of SMN protein from the SMN2 gene (5,10,11). Species other than man have only one SMN gene, which is the equivalent of the human SMN1 gene (12,13). In mice, a homozygous knockout of the Smn gene results in early embryonic lethality following massive cell death (14). This, coupled with the fact that SMA patients lacking SMN2 have never been reported, suggests that SMN plays an essential role during embryonic development. We and others (15,16) have previously shown that sequence differences in the promoters of the SMN genes do not explain the difference in function between them. Instead the critical difference between the two genes is a single nucleotide change in exon 7 that causes this exon to be spliced out of the majority of the transcript from SMN2. On the other hand, most of the transcript from SMN1 is full length (17,18). Patients with milder forms of SMA have more copies of the SMN2 gene than those with more severe forms of SMA, indicating that it can act as a phenotypic modifier (19, and references therein).
The 38 kDa SMN protein is ubiquitously expressed and is found in both cytoplasm and nucleus. Intranuclear SMN is found concentrated in aggregates called gems (20). The exact function of SMN remains unknown, but it has been shown to interact with the protein SIP-1 and several spliceosomal snRNP core proteins (21,22) and to play a critical role in spliceosomal snRNP assembly in the cytoplasm, most likely functioning in the regeneration/recycling of snRNPs and other splicing factors (23). In type I SMA patients SMN protein levels are severely reduced and cells lack gems (10,11).
Although SMN is ubiquitously expressed, the exact reasons why motor neurons are selectively affected are not clear. To understand further the molecular pathology of SMA it is important to understand the role of exon 7 in SMN, the effects of SMN dosage on motor neuron survival and whether SMN2 is capable of rescuing early embryonic lethality in the mouse Smn–/– knockout. This can be addressed by making a mouse model of SMA. To generate such a model, we have introduced the entire human SMN2 gene onto the null Smn–/– background. This mimics the situation in human SMA patients where SMN is present at all times albeit at greatly reduced levels. We show that when the SMN2 transgene is present in low copy number on the Smn–/– background, a mouse with pathology similar to type I SMA patients results. This is the first report of an animal model of human SMA.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Construction of transgenes and genotype–phenotype analysis.
We have previously shown that the entire human SMN2 gene including its promoter lies on a 35.5 kb BamHI fragment in the genomic clone PAC 215P15 (18) (Fig. 1A). This BamHI fragment was excised out of PAC 215P15 and microinjected into fertilized mouse oocytes. Four founders out of a total of 62 potential transgenic animals were obtained. One of these died prematurely and a second failed to transmit the transgene to her offspring. The remaining two were bred to C57Bl 6J Smn+/– mice to produce Smn+/–;SMN2 progeny. The copy number of the transgenes was estimated by Southern blotting of DNA isolated from tail tissue. Based on densitometric analysis, hemizygous mice from lines 89 and 566 carry one and eight SMN2 copies, respectively (Fig. 1B).
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The early embryonic lethality seen in Smn knockout mice created by Schrank et al. (14) probably results when maternal SMN is depleted. To test whether the SMN2 transgene could rescue this embryonic lethality and produce a mouse with SMA, we initially mated our transgenic mice with Smn+/– mice. F1 offspring carrying an Smn knockout allele and the SMN2 transgene were then interbred to produce F2 progeny. Approximately 15% (46/312) of the F2 progeny derived from the low copy founder, 89, were either stillborn or died within 6 h of birth (Table 1). The vast majority (42/46) of these mice were shown by genotyping to carry one or two copies of the transgene and be homozygous for the Smn knockout allele (Smn–/–;SMN2). In fewer cases (14/312), Smn–/–;SMN2 pups survived for up to 6 days of age. A total of 18% (56/312) of the progeny were found to be of the genotype Smn–/–;SMN2. This is slightly lower than the expected frequency (20%) for this genotype if both parents are heterozygous for SMN2. However, this may be explained by some death occurring in utero.
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At birth the low copy Smn–/–;SMN2 mice looked phenotypically normal. Mice stillborn or those that die shortly after birth were slightly smaller (average weight = 1.33 g, n = 5) than normal littermates (average weight = 1.51 g, n = 5). The stillborn mice were often cyanotic. Affected Smn–/–;SMN2 mice that survived for 4–6 days appeared phenotypically indistinguishable from littermates in the first 48 h after birth. This period was followed by a rapid deterioration in the next 48–72 h and death. These mice began to show decreased movement, decreased or lack of suckling and laboured breathing by 48 h postnatal. By 72–96 h after birth the mice showed a marked phenotype including a tremor in the limbs. At this stage Smn–/–;SMN2 mice could be readily distinguished from their normal littermates (Fig. 2). Removing some unaffected littermates at 3 days of age to prevent competition for food and warmth did not increase survival of Smn–/–;SMN2 mice. When placed on their side, affected mice had difficulty righting themselves. Some Smn–/–;SMN2 also had a bell-shaped trunk, likely attributable to intercostal muscle weakness, a characteristic feature of type I SMA (24). Smn–/–;SMN2 mice died 4–6 days after birth by which time they were considerably smaller (average weight = 1.47 g, n = 4) than littermates (average weight = 4.59 g, n = 5) positive for murine Smn.
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A similar breeding strategy was followed with mice derived from the high copy number transgene, 566. At birth Smn–/– mice carrying the high copy transgene did not show any obvious phenotype. At the time of going to press two of these mice are 10 months old and still do not display any overt weakness. The only unusual phenotypic feature of these mice is a short, thick tail. This becomes evident at ~2 weeks of age; however, we are unsure of the significance of this to SMA pathology. It is therefore clear that the SMN2 gene is capable of rescuing the embryonic lethality of the Smn–/– knockout. Our results demonstrate that an increased copy number of the SMN2 gene greatly reduces the severity of the phenotype seen in the low copy transgenic mice.
Expression of SMN2 in transgenic animals.
In humans, the SMN genes have been shown to be ubiquitously expressed. In addition, it has been shown that there are several alternatively spliced isoforms of SMN (25). The SMN2 gene produces all four isoforms, the predominant form being that lacking exon 7. To examine SMN2 transgene expression, 1–2 µg of poly(A)+ RNA, obtained from brain, liver and spinal cord of 4-day-old Smn–/– mice carrying the low copy transgene and adult Smn–/– individuals carrying the high copy transgene, was hybridized at high stringency with an SMN cDNA probe spanning exons 6–8. The SMN2 transgenes were ubiquitously expressed in all tissues examined (Fig. 3A). This is similar to the observed expression pattern for endogenous SMN2. Semi-quantitative reverse transcription–polymerase chain reaction (RT–PCR) using primers in exons 4 and 8 also showed that the SMN2 transgenes in both lines 89 and 566 produce the expected size transcripts in the correct ratios (Fig. 3B). Like endogenously expressed human SMN2, most of the transcripts from the transgenes lacked exon 7.
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To examine the expression of the SMN protein from the SMN2 transgenes, liver (data not shown) and brain tissue from low copy Smn–/–;SMN2, high copy Smn–/–;SMN2 and normal controls was used for western blot analysis. Our results clearly show that low copy Smn–/–;SMN2 mice have vastly reduced levels of the SMN protein (Fig. 3C). Compared with age-matched controls, these affected mice express 10- to 20-fold less SMN protein. This is consistent with previous reports of comparisons between normal human individuals and type I SMA patients (10,11). It is also interesting to note that there is a pronounced decrease in SMN protein levels in the low copy Smn–/–;SMN2 mice with the progression of age from embryonic day 15 to postnatal day 4. In control mice there was a similar although less pronounced change in SMN levels. A change in SMN levels during development has also been reported in humans (26). These results and our current observations indicate that SMN expression is developmentally regulated. A comparison of the high copy Smn–/–;SMN2 transgenic mice with controls shows that they produce equivalent levels of SMN protein. If, as suggested in earlier reports (10,11), SMA disease severity is modulated by SMN protein levels, then it is not surprising that the high copy Smn–/–;SMN2 transgenic mice are phenotypically normal.
Severe loss of motor neurons in low copy Smn–/–;SMN2.
One of the most striking neuropathological features of infantile SMA is the degeneration of the motor neurons of the spinal cord and the lower brain stem. However, the timing of this motor neuron death in SMA is unknown. To determine whether our mice, in particular the low copy Smn–/–;SMN2 ones, suffer a loss of these motor neurons, animals between the ages of 1 and 5 days were sacrificed and perfused, and their motor neurons in the spinal cord and facial nucleus counted in paraffin-embedded serial sections. Interestingly, we found relatively normal numbers of motor neurons in the spinal cord and facial nucleus of 1-day-old high and low copy Smn–/–; SMN2 mice compared with age-matched controls (Table 2). However, by postnatal day 5, there was a dramatic loss of these cells in the low copy Smn–/–;SMN2 mice. This degeneration varied from an ~35% loss in the spinal cord to a 40% loss in the facial nucleus. In addition, increased numbers of apparently dying cells with pyknotic nuclei were evident in the spinal cords and facial nuclei of these mice (Fig. 4A, D and G). This indicates that motor neurons develop normally in SMN-deficient mice and undergo death in the latter stages of the disease. The loss of motor neurons in the older low copy Smn–/–;SMN2 mice parallels the appearance of the disease phenotype. This loss begins at postnatal day 3. However, subtle degenerative changes in the motor neurons may begin prior to this since most of our low copy Smn–/–;SMN2 mice were stillborn or died very shortly after birth. In Smn–/–;SMN2 mice that survived for 4–6 days, the motor neurons apparently reached a crisis stage ~3 days after birth and were rapidly lost thereafter.
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A second characteristic feature of SMA patients is the presence of atrophic muscle fibers. We examined the quadriceps and gastrocnemius muscle of 4- to 5-day-old low copy Smn–/–;SMN2 mice but did not find any remarkable pathology (data not shown). This may be because muscle in very young rodents undergoes polyneuronal innervation which is lost at ~2 weeks of age (27 and references therein). Loss of motor neurons may, therefore, begin to occur before shrinkage of motor unit size leads to denervated muscle. An examination of the gastrocnemius and quadriceps muscles from the high copy Smn–/–;SMN2 mice showed no pathology even at the age of 2 months.
Absence of gems in low copy Smn–/–;SMN2 mice
. Finally we sought to examine SMN2 expression in the spinal motor neurons of our transgenic mice by immunohistochemical methods. It has been shown previously that SMN localizes to subnuclear structures termed gems. Further, it has been reported that there is a high correlation between clinical severity of the SMA phenotype and the number of gems in patient fibroblasts and spinal cord. To determine whether this is the case in our Smn–/–;SMN2 transgenic mice, lumbar spinal cord sections from 5-day-old animals were stained with anti-SMN monoclonal antibodies and visualized by fluorescence microscopy. Neonatal mice had reduced cytoplasmic staining as well as less intense and smaller gems than adult mice. It is clear from our results that the low copy Smn–/–;SMN2 mice had almost no gems in the spinal motor neurons compared with the high copy Smn–/–;SMN2 animals and normal controls (Fig. 5). Fibroblasts derived from the low copy Smn–/–;SMN2 also showed no gems (data not shown). This is similar to observations of fibroblasts and spinal cord sections from type I SMA patients and re-inforces our view that the low copy Smn–/–;SMN2 transgenic mice serve as a suitable animal model of severe infantile SMA. Moreover, unlike previously described animal models of human SMA (28,29), ours is the first that involves alterations in the mouse homolog of the SMN1 gene and low levels of the SMN protein.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The presence of at least one intact SMN2 gene in SMA patients and the early embryonic lethality in Smn–/– mice strongly suggested that low SMN levels are essential for development. Here we provide the first direct evidence that the SMN2 gene can rescue the embryonic lethality in Smn–/– mice and allow development to progress to term. Our study shows that low levels of SMN protein, such as those found in type I SMA patients, are sufficient for embryonic development. Motor neuron cells which are particularly sensitive to low levels of SMN produced by the SMN2 gene are lost in the postnatal period. This includes spinal motor neurons as well as those in the facial nucleus. Loss of the latter has not been reported in the literature in studies of human type I SMA patients. Perhaps this is due to the fact that these studies are based on limited numbers of patients that were either clinically poorly characterized or heterogeneous in presentation (27). It would not be surprising to find loss of this subset of motor neurons in SMA patients if a detailed analysis including morphometric counts was carried out. We would also note that although specific motor neuron counts have not been carried out on human type I SMA patients of different ages, it is quite likely that motor neuron death in these individuals occurs at similar points in development as that observed in our low copy Smn–/–; SMN2 mice. The fact that the disease often presents with such sudden onset after relatively normal development (27) strengthens this view.
We have shown using our high copy Smn–/–;SMN2 transgenic mice that an increased expression of the SMN protein, even if it is from the SMN2 gene, is capable of rescuing the SMA phenotype. This result is consistent with the observation that in human SMA there is a correlation between phenotypic severity and SMN2 copy number and supports the hypothesis that the SMN2 gene acts as a modifier of phenotype (30,31). In addition there is a report of a very mildly affected 70-year-old SMA patient who has eight copies of the SMN2 gene (32). This also supports our data regarding the importance of SMN dosage in determining phenotypic severity.
In summary, we have developed a mouse model whose disease symptoms and neuropathology are remarkably similar to those of severe type I SMA in humans. We have shown that motor neuron loss in low copy Smn–/–;SMN2 mice occurs postnatally and that increased SMN2 copy number rescues all overt features of type I SMA. These results suggest that increased expression from the SMN2 gene during postnatal development, before complete onset of the disease, will rescue the loss of motor neurons in SMA and decrease phenotypic severity. Our low copy Smn–/–;SMN2 mouse is the first true animal model of human SMA and will be extremely useful in testing possible candidates for the upregulation of the centromeric gene.
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MATERIALS AND METHODS |
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Microinjections and genotyping of mice.
PAC 215P15 was digested with BamHI and ClaI. ClaI serves to digest a 29 kb band that contaminates SMN2. The digested DNA was run on a 0.4% low-melt agarose gel and the 35.5 kb fragment excised out. Following purification it was resuspended in injection buffer (10 mM Tris–Cl, 0.1 M EDTA, 100 mM NaCl, 70 µM spermidine and 30 µM spermine) at a concentration of 2 ng/µl, dialyzed using a 0.05 µM membrane filter (Millipore, Bedford, MA) and then injected into fertilized FVB mouse oocytes. Copy number was assessed by Southern blot analysis of 10 µg of DNA digested with PstI and probed with an ~450 bp exon 6–8 human SMN cDNA fragment. Digested DNA was electrophoresed on a 1% agarose gel before being transferred onto Hybond N+ (Amersham, Piscataway, NJ). The probe was radioactively labeled and hybridized to the filter according to standard methods (33). The filter was washed at high stringency and then exposed to Hyperfilm MP (Amersham) with an intensifying screen. Densitometric analysis was performed on a Shimadzu 9000 CS scanner (Shimadzu, Kyoto, Japan).
Northern analysis and RT–PCR.
Mice were sacrificed by cervical dislocation and poly(A)+ RNA isolated using the QuickPrep Micro mRNA Purification kit (Amersham) according to the manufacturer’s recommendations. For northern analysis, 1–2 µg of RNA was fractionated on a 1.2% agarose–formaldehyde gel prior to blotting. The filter was prehybridized and hybridized in ExpressHyb hybridization solution (Clontech, Palo Alto, CA). It was then washed as per the manufacturer’s instructions. The probe used was the same as the one used for Southern analysis. The membrane was stripped after the first hybridization and reprobed with a 245 bp mouse ß-actin cDNA fragment to control for loading amounts. RT–PCR was carried out on 0.2 µg of first strand cDNA. Both primers were end-labeled with [
-32P]ATP and amplification performed in a 25 µl volume containing 0.5 mM dNTPs, 1 U taq polymerase, 30 ng of each of the primers and 2.5 mM Mg2+. Cycling conditions were: 95°C for 5 min; 20 cycles of 95°C for 1 min, 55°C for 2 min, 72°C for 3 min; with a final extension at 72°C for 8 min. Products were separated for 12 000 Vh on a 6% denaturing polyacrylamide gel which was dried and exposed to Hyperfilm-MP for 1–4 days.
Western blot analysis.
Tissue (100 mg) was dissolved in blending buffer (10% SDS, 62.5 mM Tris pH 6.8, 5 mM EDTA). The concentration of the protein was determined using the BCA kit (Pierce, Rockford, IL). Protein (25–50 µg) was mixed with an equal volume of sample buffer (62.5 mM Tris pH 6.8, 10% glycerol, 10% 2-mercaptoethanol, 0.4 mg of bromophenol blue) and electrophoresed on a 12.5% polyacrylamide gel. Samples were transferred to Immobilon-P (Millipore) as previously described (11). The blot was blocked in 5% milk powder, 0.5% bovine serum albumin (BSA) in TBS–Tween (TBS-T) for 2 h, then incubated for 1 h with an anti-SMN primary antibody (MANSMA2, specific for either exon 2A or 2B) dissolved in 1% milk, 0.1% BSA in TBS-T at a 1:1000 dilution. After four washes in TBS-T at room temperature (10 min each) the blot was incubated with a goat anti-mouse HRP-linked F(ab')2 antibody (Jackson Immunoresearch, West Grove, PA) at a 1:8000 dilution. The blot was again washed four times in TBS-T and then visualized using ECL chemiluminescent reagent (Amersham) according to the manufacturer’s recommendations. The blots were then stripped and reprobed with a ß-tubulin antibody (Sigma, St Louis, MO) to control for loading amounts.
Histology and immunocytochemistry.
One- to five-day-old low and high copy Smn–/–; SMN2 mice and normal controls were sacrificed and perfused with fresh 4% paraformaldehyde in phosphate-buffered saline (PBS). Tissue from these mice was embedded in paraffin according to conventional procedures. Serial sections (7 µm) prepared with an automated Leica (Nusloch, Germany) rotation microtome were mounted on glass slides and subjected to Nissl’s staining as previously described (34). Neurons within the facial nucleus and the lumbar motor column (L1–L6) were counted and tallied after correcting for double counts of split nucleoli. Whole spinal columns were mounted on wooden blocks and flash frozen in isopentane chilled to –150°C in liquid nitrogen. Sections (8 µm) were cut, mounted on superfrost slides (Fisher Scientific, Pittsburgh, PA) and air dried for 30 min. They were then rehydrated in PBS (5 min), fixed in 4% paraformaldehyde (1 min), briefly rinsed in PBS and finally treated with ice-cold acetone (5 min). Then they were air dried (30 min) and incubated with a 1:5 dilution of mouse blocker from the MOM kit (Vector Laboratories, Burlingame, CA) at room temperature for 30 min. Sections were then rinsed twice in PBS, blocked with 10% normal donkey serum (Jackson Immunoresearch) for 30 min and then incubated for 2 h with a mixture of anti-SMN antibodies MANSMA7, MANSMA6 and 8B3, diluted 1:100 in 1% donkey serum. After washing in PBS (three times, 5 min each) sections were incubated for 30 min with FITC-conjugated donkey anti-mouse F(ab')2 antibody (Jackson Immunoresearch) at a 1:50 dilution in PBS. Sections were washed again, mounted with 25 µl of Vectorshield (Vector Laboratories) containing a 1:6 dilution of DAPI and examined using a Nikon E800 microscope equipped with HiQ FITC and TRITC/DAPI dual wavelength filter sets (Chroma Technology, Battleboro, VT). Black and white images were captured with an Olympix Ultrapix digital camera (Olympus America, Melville, NY), pseudocolored and merged using the Olympus software.
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ACKNOWLEDGEMENTS |
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We thank Drs K. Rammohan and E. Rath for help with image analysis and perfusions, J. Kara for expert technical assistance, Dr M. Braga for help with motor neuron counts, and Dr J. Rafael for advice. This study was supported by Families of SMA, the Preston, Madison and Mathew funds, the Muscular Dystrophy Association of America, NIH grant no. NS 38650 to A.H.M.B. and a grant from the Deutsche Forschungsgemeinschaft (To61/8-4) to M.S.
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FOOTNOTES |
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+ These authors contributed equally to this work
§ To whom correspondence should be addressed at: Department of Medical Biochemistry, 363 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA. Tel: +1 614 688 4710; Fax: +1 614 292 4118; Email: burghes.1@osu.edu
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REFERENCES |
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J.-G. Chang, H.-M. Hsieh-Li, Y.-J. Jong, N. M. Wang, C.-H. Tsai, and H. Li Treatment of spinal muscular atrophy by sodium butyrate PNAS, August 14, 2001; 98(17): 9808 - 9813. [Abstract] [Full Text] [PDF]
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 P. SAUGIER-VEBER, N. DROUOT, S. LEFEBVRE, F. CHARBONNIER, E. VIAL, A. MUNNICH, and T. FRÉBOURG Detection of heterozygous SMN1 deletions in SMA families using a simple fluorescent multiplex PCR method J. Med. Genet., April 1, 2001; 38(4): 240 - 243. [Full Text]
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C. Cifuentes-Diaz, T. Frugier, F. D. Tiziano, E. Lacene, N. Roblot, V. Joshi, M. H. Moreau, and J. Melki Deletion of Murine SMN Exon 7 Directed to Skeletal Muscle Leads to Severe Muscular Dystrophy J. Cell Biol., March 5, 2001; 152(5): 1107 - 1114. [Abstract] [Full Text] [PDF]
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S. Jablonka, M. Bandilla, S. Wiese, D. Buhler, B. Wirth, M. Sendtner, and U. Fischer Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy Hum. Mol. Genet., March 1, 2001; 10(5): 497 - 505. [Abstract] [Full Text] [PDF]
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L. Pellizzoni, B. Charroux, J. Rappsilber, M. Mann, and G. Dreyfuss A Functional Interaction between the Survival Motor Neuron Complex and RNA Polymerase II J. Cell Biol., January 8, 2001; 152(1): 75 - 86. [Abstract] [Full Text] [PDF]
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D. A. Kerr, J. P. Nery, R. J. Traystman, B. N. Chau, and J. M. Hardwick Survival motor neuron protein modulates neuron-specific apoptosis PNAS, November 8, 2000; (2000) 230364197. [Abstract] [Full Text]
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P. J. Young, N. t. Man, C. L. Lorson, T. T. Le, E. J. Androphy, A. H.M. Burghes, and G. E. Morris The exon 2b region of the spinal muscular atrophy protein, SMN, is involved in self-association and SIP1 binding Hum. Mol. Genet., November 1, 2000; 9(19): 2869 - 2877. [Abstract] [Full Text] [PDF]
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U. R. Monani, D. D. Coovert, and A. H.M. Burghes Animal models of spinal muscular atrophy Hum. Mol. Genet., October 1, 2000; 9(16): 2451 - 2457. [Abstract] [Full Text] [PDF]
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G. Meister, D. Buhler, B. Laggerbauer, M. Zobawa, F. Lottspeich, and U. Fischer Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins Hum. Mol. Genet., August 12, 2000; 9(13): 1977 - 1986. [Abstract] [Full Text] [PDF]
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Y. Hofmann, C. L. Lorson, S. Stamm, E. J. Androphy, and B. Wirth Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2) PNAS, August 6, 2000; (2000) 160181697. [Abstract] [Full Text]
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S. Paushkin, B. Charroux, L. Abel, R. A. Perkinson, L. Pellizzoni, and G. Dreyfuss The Survival Motor Neuron Protein of Schizosacharomyces pombe. CONSERVATION OF SURVIVAL MOTOR NEURON INTERACTION DOMAINS IN DIVERGENT ORGANISMS J. Biol. Chem., July 28, 2000; 275(31): 23841 - 23846. [Abstract] [Full Text] [PDF]
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J. Wang and G. Dreyfuss A Cell System with Targeted Disruption of the SMN Gene. FUNCTIONAL CONSERVATION OF THE SMN PROTEIN AND DEPENDENCE OF Gemin2 ON SMN J. Biol. Chem., March 23, 2001; 276(13): 9599 - 9605. [Abstract] [Full Text] [PDF]
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N. Kurihara, C. Menaa, H. Maeda, D. J. Haile, and S. V. Reddy Osteoclast-stimulating Factor Interacts with the Spinal Muscular Atrophy Gene Product to Stimulate Osteoclast Formation J. Biol. Chem., October 26, 2001; 276(44): 41035 - 41039. [Abstract] [Full Text] [PDF]
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J. Wang and G. Dreyfuss Characterization of Functional Domains of the SMN Protein in Vivo J. Biol. Chem., November 21, 2001; 276(48): 45387 - 45393. [Abstract] [Full Text] [PDF]
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Y. Hofmann, C. L. Lorson, S. Stamm, E. J. Androphy, and B. Wirth Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2) PNAS, August 15, 2000; 97(17): 9618 - 9623. [Abstract] [Full Text] [PDF]
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D. A. Kerr, J. P. Nery, R. J. Traystman, B. N. Chau, and J. M. Hardwick Survival motor neuron protein modulates neuron-specific apoptosis PNAS, November 21, 2000; 97(24): 13312 - 13317. [Abstract] [Full Text] [PDF]
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