Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:Q16637 (SMA)
8,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinal muscular atrophy (SMA) is a common human inherited disease characterized by degeneration of motoneurons and muscular atrophy. SMA results from deletions or mutations of the SMN (survival motor neuron) gene. A nerve-muscle coculture model, consisting of human muscle cells innervated by rat embryonic spinal cord explants, was used to study the pathogenesis of SMA. Previous studies have shown that myotubes formed by fusion of satellite muscle cells from patients with SMA I or SMA II (but not SMA III) underwent a characteristic degeneration 1-3 weeks after innervation. To correlate this cellular study with a molecular approach, we used reverse transcriptase-polymerase chain reaction (RT-PCR), and showed that SMN mRNAs were expressed throughout the fusion of normal satellite muscle cells with two peaks, the first appearing prior to the onset of fusion and the second one or two days before innervation. When satellite muscle cells from patients with SMA I or II were used, only the first peak was observed. Because in these cases the SMN telomeric gene (SMNtel) is deleted, it was concluded that the contribution of SMNtel-dependent mRNAs to the second peak is predominant in normal myogenesis and involved in maturation of myotubes. In addition, diseased satellite muscle cells did not fuse at the same rate as normal satellite muscle cells. Studies on myf-5, a muscle specific transcription factor family, showed that its expression was impaired during the fusion of satellite muscle cells from patients with SMA I or II compared with normal satellite muscle cells. Taken together, these observations suggest that (a) there is a muscle specific expression pattern of SMN, and (b) SMN probably plays a crucial role in maintenance of a functional motor unit, by allowing muscle cells to correctly differentiate and to allow motoneuron survival.
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PMID:On the possible role of muscle in the pathogenesis of spinal muscular atrophy. 1146 11

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.
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PMID:Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. 1152 96

Mutations of the telomeric survival motor neuron gene (SMN1) are related to spinal muscular atrophy (SMA). However, no phenotype-genotype correlation has been observed since the SMN1 gene is lacking in the majority of patients affected with either the severe form (type I) or the milder forms (types II and III). Here, we analyze the SMN, NAIP and P44 genes in 132 Chinese SMA patients and their families. At least three types of normal allele, and four types of mutant allele were found in this study. The combination of one normal allele with one mutant allele resulted in carriers of different types, and the combination of different mutant alleles accounted for the different genotypes among different types of SMA. Deletions of mutant alleles can be further subgrouped into four types, which includes involving SMN1, SMN1 and NAIP(T) (telomeric portion of NAIP gene), SMN1 and NAIP(T) and P44(T) (telomeric portion of P44 gene), and SMN1 and SMN2 (centromeric portion of SMN gene). Some of the severe (type I) SMA cases correlated with the extent of deletions in the SMN, NAIP and P44 genes or the dosage of SMN gene when both SMN1 and SMN2 are deleted. We also found two novel point mutations, an A insertion at codon 8 (AGT-->AAGT) and an A substitution at codon 228 (TTA-->TAA).
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PMID:Molecular analysis of SMN, NAIP and P44 genes of SMA patients and their families. 1157 4

Spinal muscular atrophy (SMA) is a severe neurodegenerative autosomal recessive disorder, second only in frequency to cystic fibrosis. In its most severe form, SMA type I (Werdnig-Hoffman), death invariably ensues before age 2 years from respiratory failure or infection. Around 98% of clinical cases of SMA are caused by the homozygous absence of a region of exons 7 and 8 of the telomeric copy of the SMN gene (SMN1) on chromosome 5. We have developed a novel means of preimplantation diagnosis of SMA using a nested polymerase chain reaction (PCR) amplification of exon 7 of SMN, followed by a HinfI restriction digest of the PCR product enabling the important SMN1 gene to be distinguished from the centromeric SMN2 gene which has no clinical phenotype. This method was designed to reduce the likelihood of misdiagnosis. Five couples were treated using this method. Four proceeded to embryo transfer which resulted in six liveborns (one singleton, one twin and one triplet), all free of SMA. Embryo transfer was not performed in one cycle because of PCR contamination.
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PMID:Six unaffected livebirths following preimplantation diagnosis for spinal muscular atrophy. 1157 69

Spinal muscular atrophy (SMA) is a genetic disorder caused by mutations in the human survival of motor neuron 1 gene, SMN1. SMN protein is part of a large complex that is required for biogenesis of various small nuclear ribonucleoproteins (snRNPs). Here, we report that SMN interacts directly with the Cajal body signature protein, coilin, and that this interaction mediates recruitment of the SMN complex to Cajal bodies. Mutation or deletion of specific RG dipeptide residues within coilin inhibits the interaction both in vivo and in vitro. Interestingly, GST-pulldown experiments show that coilin also binds directly to SmB'. Competition studies show that coilin competes with SmB' for binding sites on SMN. Ectopic expression of SMN and coilin constructs in mouse embryonic fibroblasts lacking endogenous coilin confirms that recruitment of SMN and splicing snRNPs to Cajal bodies depends on the coilin C-terminal RG motif. A cardinal feature of SMA patient cells is a defect in the targeting of SMN to nuclear foci; our results uncover a role for coilin in this process.
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PMID:Coilin forms the bridge between Cajal bodies and SMN, the spinal muscular atrophy protein. 1164 Dec 77

Polymerase chain reaction with subsequent SSCP (single-strand DNA conformational polymorphism) and restriction (BselI restriction endonuclease) analyses were used to type the DNA samples of affected individuals and their relatives from 23 Russian families with high risk of spinal muscular atrophy (SMA) residing in the northwestern region of Russia. Deletions of exon 7 of the SMN gene were found in 96% of the individuals examined. The frequency of homozygous deletion of exons 7 and 8 of the SMN1 gene was 65%. The frequency of homozygous isolated deletion of the SMN1 gene exon 7 among the SMA patients was 4.3%. Homozygous deletion of exon 5 of the NAIP gene was found in 22% of SMA patients. In SMA patients, a total of seven deletion types involving the SMN1, NAIP, and SMN2 genes were detected. Deletion of exons 7 and 8 of the SMN1 gene was the most common mutation associated with SMA in patients from the northwestern Russia.
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PMID:[Analysis of deletional damage in SMN1, SMN2, and NAIP genes in patients with spinal muscular atrophy in the northwestern region of Russia]. 1164 17

Most spinal muscular atrophy patients lack both copies of SMN1 exon 7 and most carriers have only one copy of SMN1 exon 7. We investigated the effect of SMN1/SMN2 heteroduplex formation on SMN gene dosage analysis, which is an assay to determine copy number of SMN1 exon 7 that utilizes multiplex quantitative polymerase chain reaction (PCR) with DraI digestion to differentiate SMN1 from SMN2. Heteroduplex formation in PCR is a well-described phenomenon. In addition to demonstrating the presence of heteroduplexes by sequence analysis of purified SMN1 bands, we compared the SMN1 signals in various genotype groups (total n = 260) to those in a group lacking SMN2 (n = 13), and we estimated the relative amounts of SMN1/SMN2 heteroduplexes. The SMN1 signal increased as SMN2 copy number increased despite a constant SMN1 copy number, although not all pairwise comparisons showed a statistically significant difference in the SMN1 signal. In conclusion, SMN1/SMN2 heteroduplexes form in SMN gene dosage analysis, falsely increasing the SMN1 signal. External controls for SMN gene dosage analysis should be chosen carefully with regard to SMN2 copy number. The effect of heteroduplex formation should be considered when performing quantitative multiplex PCR.
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PMID:Heteroduplex formation in SMN gene dosage analysis. 1168 98

Mutations in the SMN1 (survival motor neuron 1) gene cause spinal muscular atrophy (SMA). We now show that SMN protein, the SMN1 gene product, interacts directly with the tumor suppressor protein, p53. Pathogenic missense mutations in SMN reduce both self-association and p53 binding by SMN, and the extent of the reductions correlate with disease severity. The inactive, truncated form of SMN produced by the SMN2 gene in SMA patients fails to bind p53 efficiently. SMN and p53 co-localize in nuclear Cajal bodies, but p53 redistributes to the nucleolus in fibroblasts from SMA patients. These results suggest a functional interaction between SMN and p53, and the potential for apoptosis when this interaction is impaired may explain motor neuron death in SMA.
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PMID:A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy. 1170 67

Spinal muscular atrophy (SMA) is a degenerative motor neuron disorder resulting from homozygous loss of the SMN1 gene. SMN2, a nearly identical copy gene, is preserved in SMA patients. A single nucleotide difference between SMN1 and SMN2 causes exon 7 skipping in the majority of SMN2 mRNA. Gene therapy through modulation of SMN2 gene transcription in SMA patients may be possible. We constructed a series of SMN mini-genes comprised of SMN exon 6 to exon 8 sequences fused to green fluorescence protein (GFP) or luciferase reporters, to monitor SMN exon 7 splicing. These reporters recapitulated the splicing patterns of the endogenous SMN gene in stable cell lines. The SMN1-luciferase reporter was approximately 3.5-fold more active than SMN2-luciferase and SMN1-GFP intensities were visually distinguishable from SMN2-GFP. We have screened chemical inducers and inhibitors of kinase pathways using stable SMN-reporter lines and found that the phosphatase inhibitor sodium vanadate specifically stimulated exon 7 inclusion within SMN2 mRNAs. This is the first compound identified that can stimulate exon 7 inclusion into transcripts derived from the endogenous SMN2 gene. These results demonstrate that this system can be utilized to identify small molecules that regulate the splicing of SMN exon 7.
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PMID:An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA. 1170 13

Proximal spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron gene (SMN1). In humans, two nearly identical copies of SMN exist and differ only by a single non-polymorphic C-->T nucleotide transition in exon 7. SMN1 contains a 'C' nucleotide at the +6 position of exon 7 and produces primarily full-length SMN transcripts, whereas SMN2 contains a 'T' nucleotide and produces high levels of a transcript that lacks exon 7 and a low level of full-length SMN transcripts. All SMA patients lack a functional SMN1 gene but retain at least one copy of SMN2, suggesting that the low level of full-length protein produced from SMN2 is sufficient for all cell types except motor neurons. The murine Smn gene is not duplicated or alternatively spliced. It resembles SMN1 in that the critical exon 7 +6 'C' nucleotide is conserved. We have generated Smn minigenes containing either wild-type Smn exon 7 or an altered exon 7 containing the C-->T nucleotide transition to mimic SMN2. When expressed in cultured cells or transgenic mice, the wild-type minigene produced only full-length transcripts whereas the modified minigene alternatively spliced exon 7. Furthermore, Smn exon 7 contains a critical AG-rich exonic splice enhancer sequence (ESE) analogous to the human ESE within SMN exon 7, and subtle mutations within the mESE caused a variation in Smn transcript levels. In summary, we show for the first time that the murine Smn locus can be induced to alternatively splice exon 7. These results demonstrate that SMN protein levels can be varied in the mouse by the introduction of specific mutations at the endogenous Smn locus and thereby lay the foundation for developing animals that closely 'resemble' SMA patients.
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PMID:Regulation of murine survival motor neuron (Smn) protein levels by modifying Smn exon 7 splicing. 1172 60


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