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 is caused by mutations in the SMN1 gene, the product of which is part of a multi-component complex involved in the assembly of small nuclear ribonucleoproteins. A recent study indicates that SMN may also play a role in pre-mRNA splicing.
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PMID:RNA splicing: more clues from spinal muscular atrophy. 1007 19

Spinal muscular atrophy (SMA) is a common autosomal recessive disorder that results in the degeneration of spinal motor neurons. SMA is caused by alterations of the survival motor neuron ( SMN ) gene which encodes a novel protein of hitherto unclear function. The SMN protein associates with ribonucleoprotein particles involved in RNA processing and exhibits an RNA-binding capacity. We have isolated the zebrafish Danio rerio and nematode Caenorhabditis elegans orthologues and have found that the RNA-binding capacity is conserved across species. Purified recombinant SMN proteins from both species showed selectivity to poly(G) homopolymer RNA in vitro, similar to that of the human protein. Studying deletions of the zebrafish SMN protein, we defined an RNA-binding element in exon 2a, which is highly conserved across species, and revealed that its binding activity is modulated by protein domains encoded by exon 2b and exon 3. Finally, the deleted recombinant zebrafish protein mimicking an SMA frameshift mutation showed a dramatic change in vitro in the formation of the RNA-protein complexes. These observations indicate that the RNA-binding capacity of SMN is an evolutionarily conserved function and further support the view that defects in RNA metabolism most likely account for the pathogenesis of SMA.
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PMID:The RNA-binding properties of SMN: deletion analysis of the zebrafish orthologue defines domains conserved in evolution. 1019 66

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the homozygous absence of the telomeric copy of the survival motor neuron (SMNt) gene, due to deletion, gene conversion or point mutation. SMNt and its homologous centromeric copy (SMNc) encode the SMN protein, which is diffusely present in the cytoplasm and in dot-like structures, called gems, in the nucleus. We have studied the SMN protein in different cell cultures, including fibroblasts, amniocytes and CVS cells from SMA individuals and controls. By immunofluorescence analysis we found a marked reduction in the number of gems in fibroblasts, amniocytes and chorionic villus cells of all SMA patients and foetuses, independent of the type of the genetic defect. We also show that immunolocalisation of the SMN protein may be a useful tool for the characterisation of particular patients of uncertain molecular diagnosis.
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PMID:SMN protein analysis in fibroblast, amniocyte and CVS cultures from spinal muscular atrophy patients and its relevance for diagnosis. 1023 6

SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNDelta7 is partially defective for self-association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.
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PMID:A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. 1033 83

Proximal spinal muscular atrophy (SMA) is caused by mutations in the telomeric (SMNT), but not centromeric (SMNC), survival motor neuron gene. Here we have identified and analyzed the two SMN promoters. We show that a 750-bp 5'-flanking fragment from each is capable of driving expression from a reporter construct. Within this fragment, we define a approximately 200-bp element that results in high expression in a motor neuron cell line. Sequence comparison of a 3. 4-kb upstream fragment from each gene shows minimal differences. Although these differences produce a 2-fold difference in reporter activity between the two promoters, this is not sufficiently high to explain why SMNT, but not SMNC, is the disease determining gene. Our data thus demonstrate, for the first time, almost complete equivalence between the SMN promoters and rule out the important possibility that differences in them might explain why mutations in only the telomeric SMN gene cause SMA.
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PMID:Promoter analysis of the human centromeric and telomeric survival motor neuron genes (SMNC and SMNT). 1036 16

Spinal muscular atrophy (SMA) is a recessive disorder characterized by loss of motor neurons in the spinal cord. It is caused by mutations in the telomeric survival motor neuron 1 ( SMN1 ) gene. Alterations within an almost identical copy gene, the centromeric survival motor neuron 2 ( SMN2 ) gene produce no known phenotypic effect. The exons of the two genes differ by just two nucleotides, neither of which alters the encoded amino acids. At the genomic level, only five nucleotides that differentiate the two genes from one another have been reported. The entire genomic sequence of the two genes has not been determined. Thus, differences which might explain why SMN1 is the SMA gene are not readily apparent. In this study, we have completely sequenced and compared genomic clones containing the SMN genes. The two genes show striking similarity, with the homology being unprecedented between two different yet functional genes. The only critical difference in an approximately 32 kb region between the two SMN genes is the C->T base change 6 bp inside exon 7. This alteration but not other variations in the SMN genes affects the splicing pattern of the genes. The majority of the transcript from the SMN1 locus is full length, whereas the majority of the transcript produced by the SMN2 locus lacks exon 7. We suggest that the exon 7 nucleotide change affects the activity of an exon splice enhancer. In SMA patients, the loss of SMN1 but the presence of SMN2 results in low levels of full-length SMN transcript and therefore low SMN protein levels which causes SMA.
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PMID:A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. 1036 62

Spinal muscular atrophy (SMA) is caused by homozygous absence of the telomeric copy of the survival motor neuron (SMNt) gene. SMNt and its homologous centromeric copy (SMNc) encode the SMN protein, which is markedly reduced in SMA I patients. We have performed SMN transcript and protein studies on spinal cord sections of an SMA I patient using in situ hybridization and immunofluorescence. While the amount of protein was negligible, the level of transcripts was comparable with that of controls. These findings suggest that the reduced protein level is not caused by a deficient transcription of the SMNc gene.
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PMID:The drastic reduction of SMN protein in SMA I spinal cord motor neurons is not due to inefficient transcription. 1036 85

Results of analysis of chimeric SMN genes among some high SMA-risk families from Ukraine using the EcoRV and DdeI restriction enzyme hydrolysis of PCR products is presented. Chimeric cen/telSMN gene was detected in probands with homozygous deletions of telSMN exon 7 only, as well in proband with absent of homozygous deletion of exons 7 and/or 8 of the SMN gene. Effectivity of approach of detection of chimeric SMN genes based on the EcoRV and DdeI restriction enzyme analysis of PCR products and mechanisms of formation of chimeric SMN genes are discussed.
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PMID:[An analysis of chimeric SMN genes--new possibilities in the study of the molecular genetic nature of mutations and in the diagnosis of spinal muscular atrophy (SMA)]. 1047 59

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder which presents with various clinical phenotypes ranging from severe to very mild. All forms are caused by the homozygous absence of the survival motor neuron ( SMN1 ) gene. SMN1 and a nearly identical copy ( SMN2 ) are located in a duplicated region at 5q13 and encode identical proteins. The genetic basis for the clinical variability of SMA remains unclear, but it has been suggested that the copy number of SMN2 could influence the disease severity. We have assessed the number of SMN2 genes in patients with different clinical phenotypes by fluorescence in situ hybridization (FISH) using as SMN probe a mixture of small specific DNA fragments. Gene copy number was established by FISH on interphase nuclei, but the presence of two SMN2 genes on the same chromosome could also be revealed by FISH on metaphase spreads. All patients had at least two SMN2 genes. We found two or three copies of SMN2 in severely affected type I patients, three copies in intermediately affected type II patients, generally four copies in mildly affected type III patients and four or eight copies in patients with very mild adult-onset SMA. No alterations of the genes were detected by Southern blot and sequence analysis, suggesting that all gene copies of SMN2 were intact. These data provide additional evidence that the SMN2 genes modulate the disease severity and suggest that knowledge of the gene copy number could be of some prognostic value.
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PMID:Detection of the survival motor neuron (SMN) genes by FISH: further evidence for a role for SMN2 in the modulation of disease severity in SMA patients. 1055 1

The survival motor neuron genes, SMN1 and SMN2, encode identical proteins; however, only homo- zygous loss of SMN1 correlates with the development of spinal muscular atrophy (SMA). We have previously shown that a single non-polymorphic nucleotide difference in SMN exon 7 dramatically affects SMN mRNA processing. SMN1 primarily produces a full-length RNA whereas SMN2 expresses dramatically reduced full-length RNA and abundant levels of an aberrantly spliced transcript lacking exon 7. The importance of proper exon 7 processing has been underscored by the identification of several mutations within splice sites adjacent to exon 7. Here we show that an AG-rich exonic splice enhancer (ESE) in the center of SMN exon 7 is required for inclusion of exon 7. This region functioned as an ESE in a heterologous context, supporting efficient in vitro splicing of the Drosophila double-sex gene. Finally, the protein encoded by the exon-skipping event, Delta7, was less stable than full-length SMN, providing additional evidence of why SMN2 fails to compensate for the loss of SMN1 and leads to the development of SMA.
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PMID:An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. 1060 36


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