Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The goal of this study was to define the correlation between genotype and phenotype in Korean patients with spinal muscular atrophy (SMA). The SMA can be classified into three groups based on the age of onset and the clinical course. The candidate genes, survival motor neuron (SMN) gene, neuronal apoptosis inhibitory protein (NAIP) gene, and p44 gene were mapped and duplicated with telomeric and centromeric. The loss of the telomeric SMN occurs by a different mechanism. That is the deletion or conversion of telomeric SMN to centromeric SMN, in which case the conversion could produce a mild phenotype and deletion could produce a severe one. It has been known that there may be a balance between the numbers of copies expressed by the centromeric and telomeric SMN genes. In our study, ten patients with type I SMA and two type II patients were identified by their clinical findings and DNA studies. The major deletion of SMA candidate genes, deletion of the SMN gene, NAIP gene, and p44 gene were identified in six patients with type I SMA, while the rest of type I and all the type II patients showed the deletion of the SMN gene only. Allele numbers of the C212 marker were compared in patients and normal controls in order to find the correlation between the copy numbers and the clinical severity. The result was that type I patients had 2-5 alleles and the normal controls had 4-6. This suggests that the deletion is a major determining factor in the clinical phenotype. However, two type I patients with telomeric NAIP gene deletion notably had 4-5 alleles, as in the normal controls. This result implies that the correlation between the copy numbers and the severity is uncertain as opposed to the previous hypothesis. One type I patient showed the conversion of the centromeric SMN gene to the telomeric, which supports the conclusion that gene conversion is an important molecular mechanism for SMA. In the study of one hundred normal newborns, two physically normal newborns showed deletion of the centromeric SMN gene, suggesting frequent rearrangement in the locus.
Mol Cells 2001 Feb 28
PMID:Correlation between genotype and phenotype in Korean patients with spinal muscular atrophy. 1126 16

The survival of motor neurons protein (SMN), the product of the neurodegenerative disease spinal muscular atrophy (SMA) gene, functions as an assembly factor for snRNPs and likely other RNPs. SMN binds the arginine- and glycine-rich (RG) domains of the snRNP proteins SmD1 and SmD3. Specific arginines in these domains are modified to dimethylarginines, a common modification of unknown function. We show that SMN binds preferentially to the dimethylarginine-modified RG domains of SmD1 and SmD3. The binding of other SMN-interacting proteins is also strongly enhanced by methylation. Thus, methylation of arginines is a novel mechanism to promote specific protein-protein interactions and appears to be key to generating high-affinity SMN substrates. It is reasonable to expect that protein hypomethylation may contribute to the severity of SMA.
Mol Cell 2001 May
PMID:SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. 1138 57

To study whether moderate under-nutrition causes muscle wasting, reindeer (Rangifer tarandus tarandus L.) calves were fed either pelleted reindeer feed ad libitum (n=8) or restricted amounts of lichens (n=8). The restricted amount was 60% of ad libitum intake of lichens, and the feeding period was 6 weeks preceded by a 2-week adjustment period. Biopsy samples from the middle gluteal muscle (M. gluteus medius) for the analysis of fibre composition and area, as well as for the activity of cathepsin B were taken before the restriction period in November and January, and after the restriction period in April. In all calves the muscle fibre composition remained unchanged during the winter. In the lichen group, the fibre size also remained unchanged, whereas in control calves the cross sectional area of type I and type IIA fibres increased significantly from November to April. Cathepsin B activity decreased in all calves from November to January and remained at that low level for the rest of the study period, which suggests an attenuated rate of protein degradation. These results can be taken as an indication that moderate under-nutrition causes no muscle wasting in reindeer calves, and the decreased availability of nitrogen is partially compensated for by adaptive decrease in protein degradation. Interestingly the adaptive changes in protein metabolism are equally well seen in the well-fed controls as in the undernourished lichen-fed reindeer.
Comp Biochem Physiol A Mol Integr Physiol 2001 Jun
PMID:Muscle fibre growth in undernourished reindeer calves (Rangifer tarandus tarandus L.) during winter. 1142 19

Myotonic dystrophy type 1 (DM1) is a dominant neuromuscular disorder caused by a trinucleotide (CTG) repeat expansion. Mutant DMPK 3'-untranslated region (3'-UTR) transcripts aggregate in nuclear foci and are thought to impose dominant-negative effects by interacting with RNA binding proteins. We demonstrated previously that the mutant 3'-UTR RNA disrupted C2C12 myoblast differentiation, and that the CUG expansion was necessary for this effect. Several proteins are known to interact with the CUG tract or the region 3' (distal) to it. Here, using a library of transfected C2C12 clones, we show that although transcripts containing a CUG expansion alone or a CUG expansion plus the distal region of the DMPK 3'-UTR accumulate into RNA foci, neither of these RNAs affect C2C12 myogenesis. Thus, RNA foci formation, and perturbation of any RNA binding factors involved in this process, are not sufficient to block myoblast differentiation. Interestingly, we found that transcripts containing expanded CUG tracts can form both nuclear and cytoplasmic RNA foci, demonstrating that factors involved in foci formation are present in the nucleus and cytoplasm. RNA analysis of myogenic markers revealed that the mutant DMPK 3'-UTR mRNA does not affect myoblast determination factors MyoD or Myf5, but significantly impedes upregulation of the differentiation factors myogenin and p21. C2C12 provide a good model to study adult muscle regeneration. Our observations in this system may be relevant to the lack of a regenerative response to continued muscle wasting in DM, and point to defects in early events in the myogenic response to muscle damage.
Hum Mol Genet 2001 Sep 01
PMID:The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. 1155 24

Amyotrophic lateral sclerosis (ALS) is mainly a sporadic neurodegenerative disorder characterized by loss of cortical and spinal motoneurons. Some familial ALS cases (FALS) have been linked to dominant mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Transgenic mice overexpressing a mutated form of human SOD1 with a Gly93Ala substitution develop progressive muscle wasting and paralysis as a result of spinal motoneuron loss and die at 5 to 6 months. We investigated the effects of neurotrophic factor gene delivery in this FALS model. Intramuscular injection of an adenoviral vector encoding cardiotrophin-1 (CT-1) in SOD1G93A newborn mice resulted in systemic delivery of CT-1, supplying motoneurons with a continuous source of trophic factor. CT-1 delayed the onset of motor impairment as assessed in the rotarod test. Axonal degeneration was slowed and skeletal muscle atrophy was largely reduced by CT-1 treatment. By monitoring the amplitude of the evoked motor response, we showed that the time-course of motor impairment was significantly decreased by CT-1 treatment. Thus, adenovirus-mediated gene transfer of neurotrophic factors might delay neurogenic muscular atrophy and progressive neuromuscular deficiency in ALS patients.
Hum Mol Genet 2001 Sep 01
PMID:Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice. 1155 29

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.
J Mol Diagn 2001 Nov
PMID:Heteroduplex formation in SMN gene dosage analysis. 1168 98

snRNPs, integral components of the pre-mRNA splicing machinery, consist of seven Sm proteins which assemble in the cytoplasm as a ring structure on the snRNAs U1, U2, U4, and U5. The survival motor neuron (SMN) protein, the spinal muscular atrophy disease gene product, is crucial for snRNP core particle assembly in vivo. SMN binds preferentially and directly to the symmetrical dimethylarginine (sDMA)-modified arginine- and glycine-rich (RG-rich) domains of SmD1 and SmD3. We found that the unmodified, but not the sDMA-modified, RG domains of SmD1 and SmD3 associate with a 20S methyltransferase complex, termed the methylosome, that contains the methyltransferase JBP1 and a JBP1-interacting protein, pICln. JBP1 binds SmD1 and SmD3 via their RG domains, while pICln binds the Sm domains. JBP1 produces sDMAs in the RG domain-containing Sm proteins. We further demonstrate the existence of a 6S complex that contains pICln, SmD1, and SmD3 but not JBP1. SmD3 from the methylosome, but not that from the 6S complex, can be transferred to the SMN complex in vitro. Together with previous results, these data indicate that methylation of Sm proteins by the methylosome directs Sm proteins to the SMN complex for assembly into snRNP core particles and suggest that the methylosome can regulate snRNP assembly.
Mol Cell Biol 2001 Dec
PMID:The methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteins. 1171 66

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.
Hum Mol Genet 2001 Nov 01
PMID:Regulation of murine survival motor neuron (Smn) protein levels by modifying Smn exon 7 splicing. 1172 60

Proximal spinal muscular atrophy (SMA) is a common motor neuron disorder caused by mutation of the telomeric survival of motor neuron gene SMN1. The centromeric survival of motor neuron SMN2 gene is retained in all SMA patients but does not produce sufficient SMN protein to prevent the development of clinical symptoms. The SMN1 and SMN2 genes differ functionally by a single nucleotide change. This change affects the efficiency with which exon 7 is incorporated into the mRNA transcript. Thus, SMN2 produces less full-length mRNA and protein than SMN1. We have screened a library of compounds in order to identify ones that can alter the splicing pattern of the SMN2 gene. Here, we report that the compound aclarubicin increases the retention of exon 7 into the SMN2 transcript. We show that aclarubicin effectively induces incorporation of exon 7 into SMN2 transcripts from the endogenous gene in type I SMA fibroblasts as well as into transcripts from a SMN2 minigene in the motor neuron cell line NSC34. In type I fibroblasts, treatment resulted in an increase in SMN protein and gems to normal levels. Our results suggest that alteration of splicing pattern represents a new approach to modification of gene expression in disease treatment and demonstrate the feasibility of high throughput screens to detect compounds that affect the splicing pattern of a gene.
Hum Mol Genet 2001 Nov 15
PMID:Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. 1173 49

Cachexia is a chronic state of negative energy balance and muscle wasting that is a severe complication of cancer and chronic infection. While cytokines such as IL-1alpha, IL-1beta, and TNFalpha can mediate cachectic states, how these molecules affect energy expenditure is unknown. We show here that many cytokines activate the transcriptional PPAR gamma coactivator-1 (PGC-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of PGC-1 protein. Cytokine or lipopolysaccharide (LPS)-induced activation of PGC-1 in cultured muscle cells or muscle in vivo causes increased respiration and expression of genes linked to mitochondrial uncoupling and energy expenditure. These data illustrate a direct thermogenic action of cytokines and p38 MAP kinase through the transcriptional coactivator PGC-1.
Mol Cell 2001 Nov
PMID:Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. 1174 33


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