Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Proximal spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of anterior horn cells in the spinal cord leading to weakness and wasting of voluntary muscles. Here we present the molecular analysis of both SMA candidate genes, the survival motor neuron gene (SMN; exons 7 and 8) and the neuronal apoptosis inhibitory protein gene (NAIP; exons 5, 6 and 13), in 195 patients and 348 parents of SMA families mainly of German origin. The SMN gene is homozygously deleted for both exons 7 and 8 or exon 7 only in 96% of type I SMA, 94% of type II SMA and 82% of type III SMA as well as in 0.3% of SMA parents. The NAIP gene is homozygously deleted in 46% of type I SMA, 17% of type II SMA, 7% of type III SMA and 2% of SMA parents. The frequencies of deletions in patients for both genes, SMN and NAIP, correspond to those for the NAIP gene only. SMA patients of this series who did not show deletions were clinically indistinguishable from deleted patients. In addition to one unaffected mother of a type II SMA patient, we found homozygous deletions of the SMN gene exons 7 and 8 in six further unaffected individuals, all sibs of type II and III patients. These belonged to four families with affected and unaffected sibs who showed identical haplotypes for all SMA flanking markers; therefore, we had regarded these families as chromosome 5 unlinked. All seven unaffected individuals in whom we detected SMA deletions do not show any signs of muscle weakness and are physically inconspicuous. The largest divergence between age at onset of an affected subject and the present age of unaffected deleted sibs is four decades now. The occurrence of SMN deletions in unaffected individuals suggests that other genes or mechanisms may be necessary to produce the SMA phenotype.
Hum Mol Genet 1995 Oct
PMID:Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. 859 17

In an analysis of 30 families affected by spinal muscular atrophy (SMA) we have used the solid-phase minisequencing method to determine the ratio between the number of telomeric and centromeric copies of the survival motor neuron gene (SMN and cBCD541 respectively) on normal and SMA chromosomes. This has enabled us to establish haplotypes with regard to SMN and cBCD541, and estimate their frequencies, on both types of chromosomes. Six predominant haplotypes were identified, three for normal chromosomes and three for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of cBCD541. We found evidence for the presence of patients homozygous for a deletion of SMN and with only one copy of cBCD541, but found none deleted for all copies of this gene. Several asymptomatic carriers of SMA with only a single copy of SMN and no copy of cBCD541 were identified. We could not confirm the hypothesis that the presence of more copies of cBCD541 is correlated to a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of cBCD541 were found to differ significantly between normal and SMA chromosomes. This distribution can be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes. This first report of a direct haplotype analysis of SMN and cBCD541 should help clarify the role of cBCD541 in the pathogenesis of SMA.
Hum Mol Genet 1997 Jan
PMID:Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy. 900 76

Spinal muscular atrophy (SMA) is a motor neuron disorder resulting from anterior horn cell death. Survival motor neuron ( SMN ) is the SMA-determining gene and is deleted or gene converted in >95% of SMA patients. The SMN protein has a role in spliceosomal snRNP biogenesis and has therefore been implicated indirectly in general cellular RNA processing due to its unique sub-nuclear localization within structures termed 'gems', which co-localize with spliceosomal factors within coiled bodies. In this report, direct SMN RNA-binding activity, in addition to ssDNA and dsDNA binding is demonstrated. The region of SMN encoded by exon 2 is necessary and sufficient to mediate its nucleic acid-binding activities. This domain is homologous to several nucleic acid-binding factors, including several high mobility group (HMG) proteins. Additionally, previously reported SMN missense mutations isolated from SMA patients demonstrated reduced RNA-binding activity, suggesting that nucleic acid binding is functionally significant.
Hum Mol Genet 1998 Aug
PMID:The domain encoded by exon 2 of the survival motor neuron protein mediates nucleic acid binding. 966 69

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.
Hum Mol Genet 1999 May
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 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.
Hum Mol Genet 1999 Jul
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 an inherited neuro-muscular disease characterized by specific degeneration of spinal cord anterior horn cells and subsequent muscle atrophy. Survival motor neuron ( SMN ), located on chromosome 5q13, is the SMA-determining gene. In the nucleus, SMN is present in large foci called gems, the function of which is not yet known, while cytoplasmic SMN has been implicated in snRNP biogenesis. In SMA patients, SMN protein levels and the number of gems generally correlate with disease severity, suggesting a critical nuclear function for SMN. In a screen for proteins associated with the nuclear transcription activator 'E2' of papillomavirus, two independent SMN cDNAs were isolated. The E2 and SMN proteins were found to associate specifically in vitro and in vivo. Expression of SMN enhanced E2-dependent transcriptional activation, and patient-derived SMN missense mutations reduced E2 gene expression. Our results demonstrate that SMN interacts with a nuclear transcription factor and imply that SMN may serve a role in regulating gene expression. These observations suggest that SMA may in part result from abnormal gene expression and that E2 may influence viral gene expression through SMN interaction.
Hum Mol Genet 1999 Jul
PMID:Identification of survival motor neuron as a transcriptional activator-binding protein. 1036 67

Spinal muscular atrophy (SMA) is a common disorder characterized by loss of lower motor neurones of the spinal cord. The disease is caused by mutations in the survival motor neurone ( SMN ) gene. SMN is ubiquitously expressed and evolutionarily conserved, and its role in RNA processing has been well established. However, these properties do not explain the observed specificity of motor neurone death. To gain further insight into the function of SMN, we have isolated and characterized the Caenorhabditis elegans orthologue of the SMN gene ( CeSMN ). Here we show that CeSMN is transmitted maternally as a predominantly nuclear factor, which remains present in all the blastomeres throughout embryonic development and onwards into adulthood. In adult nematodes, a CeSMN-green fluorescent protein fusion protein is expressed in a number of cell types including the germline. Both disruption of the endogenous CeSMN function and overexpression of the gene result in a severe decrease in the number of progeny and in locomotive defects. In addition, its transient knockdown leads to sterility caused by a defect in germ cell maturation. The expression pattern and functional properties so far observed for CeSMN, together with its unusual behaviour in the germline, indicate that SMN may be involved in specific gene expression events at these very early developmental stages. We have also identified a deletion in the CeSMN promoter region in egl-32. This mutant may become a useful genetic tool with which to explore regulation of CeSMN and hence provide possible clues for novel therapeutic strategies for SMA.
Hum Mol Genet 1999 Nov
PMID:The Caenorhabditis elegans orthologue of the human gene responsible for spinal muscular atrophy is a maternal product critical for germline maturation and embryonic viability. 1054 92

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.
Hum Mol Genet 1999 Dec
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.
Hum Mol Genet 2000 Jan 22
PMID:An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. 1060 36

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.
Hum Mol Genet 2000 Feb 12
PMID:The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. 1065 41


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