Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder for which there is no available therapy. SMA is caused by loss or mutation of the survival motor neuron 1 gene, SMN1, with retention of a nearly identical copy gene, SMN2. In contrast to SMN1, most SMN2 transcripts lack exon 7. This alternatively spliced transcript, Delta7-SMN, encodes a truncated protein that is rapidly degraded. Inhibiting this degradation may be of therapeutic value for the treatment of SMA. Recently aminoglycosides, which decrease translational fidelity to promote readthrough of termination codons, were shown to increase SMN levels in patient cell lines. Amid uncertainty concerning the role of SMN's C-terminus, the potential of translational readthrough as a therapeutic mechanism for SMA is unclear. Here, we used stable cell lines to demonstrate the SMN C-terminus modulates protein stability in a sequence-independent manner that is reproducible by translational readthrough. Geneticin (G418) was then identified as a potent inducer of the Delta7-SMN target sequence in vitro through a novel quantitative assay amenable to high throughput screens. Subsequent treatment of patient cell lines demonstrated that G418 increases SMN levels and is a potential lead compound. Furthermore, treatment of SMA mice with G418 increased both SMN protein and mouse motor function. Chronic administration, however, was associated with toxicity that may have prevented the detection of a survival benefit. Collectively, these results substantiate a sequence independent role of SMN's C-terminus in protein stability and provide the first in vivo evidence supporting translational readthrough as a therapeutic strategy for the treatment of SMA.
Hum Mol Genet 2009 Apr 01
PMID:Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo. 1915 Sep 90

Spinal muscular atrophy (SMA), the leading genetic cause of death in childhood, is an autosomal recessive neuromuscular disorder characterized by progressive muscle weakness, associated with deletions of the survival motor neuron (SMN) gene identified and mapped to chromosome 5q13. SMN is present in two highly homologous copies (SMN1 and SMN2). In the general population, normal individuals (noncarriers) have at least one telomeric (SMN1) copy, and 5% of them have no copies of SMN2. Approximately 95% of SMA patients carry homologous deletions of SMN1 exon(s) 7 (and 8). SMN1 and SMN2 exons 7 and 8 differ only by 1 bp each, and SMA diagnosis might be performed by single-strand conformational polymorphism, PCR amplification followed by restriction fragment length polymorphism (RFLP), multiple ligation-dependent probe amplification, or realtime PCR of SMNs exons 7 and 8. We developed a simpler and cost-effective method to detect SMN1 exon 7 deletion based on allele-specific amplification PCR.
Genet Test Mol Biomarkers 2009 Apr
PMID:A duplex allele-specific amplification PCR to detect SMN1 deletion. 1937 6

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, and about 95% of SMA patients are homozygous for deletions in the SMN1 gene. Herein, classical polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) using DraI yielded false homozygous deletions of SMN1 exon 7 in a patient with SMA, but multiple ligation-dependent probe amplification analysis revealed one remaining copy of SMN1 exon 7. Sequencing showed that this false deletion in the PCR-RFLP resulted from a novel mutation of one SMN1 copy that was not deleted (c.863G > T, p.R288M). This novel sequence variant introduced a mismatch that interfered with primer binding. These findings demonstrate that comprehensive analysis using PCR-RFLP, multiple ligation-dependent probe amplification, and sequencing can reliably and correctly diagnose SMA.
Genet Test Mol Biomarkers 2009 Aug
PMID:False homozygous deletions of SMN1 exon 7 using Dra I PCR-RFLP caused by a novel mutation in spinal muscular atrophy. 1966 1

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional protein. Antisense-mediated exon-skipping is one of the most promising approaches for the treatment of DMD because of its capacity to correct the reading frame and restore dystrophin expression, which has been demonstrated in vitro and in vivo. In particular, peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have recently been shown to induce widespread high levels of dystrophin expression in the mdx mouse model. Here, we report the efficiency of the PPMO-mediated exon-skipping approach in the utrophin/dystrophin double-knockout mouse (dKO) mouse, which is a much more severe and progressive mouse model of DMD. Repeated intraperitoneal (i.p.) injections of a PPMO targeted to exon 23 of dystrophin pre-mRNA in dKO mice induce a near-normal level of dystrophin expression in all muscles examined, except for the cardiac muscle, resulting in a considerable improvement of their muscle function and dystrophic pathology. These findings suggest great potential for PPMOs in systemic treatment of the DMD phenotype.
Mol Ther 2010 Jan
PMID:Prevention of dystrophic pathology in severely affected dystrophin/utrophin-deficient mice by morpholino-oligomer-mediated exon-skipping. 1984 93

Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder characterised by muscle weakness and atrophy due to degeneration of motor neurons of the spinal cord and cranial motor nuclei. The clinical phenotype incorporates a wide spectrum. No effective treatment is currently available and patients may experience severe physical disability which is often life limiting. The most common type of SMA is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion or mutation and results in insufficient levels of survival motor neuron (SMN) protein in motor neurons. While diagnosis is usually achieved by genetic testing, an illustrative clinical case is described that highlights the molecular and diagnostic complexities. While there is an emerging picture concerning the function of the SMN protein and the molecular pathophysiological mechanisms underpinning the disease, a number of substantial issues remain unresolved. The selective vulnerability of the motor neuron and the site and timing of the primary pathogenesis are not yet determined. Utilising the organisation of the SMN genomic region, recent advances have identified a number of potential therapeutic targets. As such, this review incorporates discussion of the clinical manifestations, molecular genetics, diagnosis, mechanisms of disease pathogenesis and development of novel treatment strategies.
Curr Mol Med 2009 Sep
PMID:Spinal muscular atrophy: molecular mechanisms. 1986 Jun 64

Neuromuscular diseases can affect the survival of peripheral neurons, their axons extending to peripheral targets, their synaptic connections onto those targets, or the targets themselves. Examples include motor neuron diseases such as amyotrophic lateral sclerosis, peripheral neuropathies, such as Charcot-Marie-Tooth diseases, myasthenias, and muscular dystrophies. Characterizing these phenotypes in mouse models requires an integrated approach, examining both the nerve and the muscle histologically, anatomically, and functionally by electrophysiology. Defects observed at these levels can be related back to onset, severity, and progression, as assessed by "quality-of-life measures" including tests of gross motor performance such as gait or grip strength. This chapter describes methods for assessing neuromuscular disease models in mice, and how interpretation of these tests can be complicated by the inter-relatedness of the phenotypes.
Methods Mol Biol 2010
PMID:Neuromuscular disease models and analysis. 2001 8

Spinal muscular atrophy (SMA), the leading genetic cause of death in childhood, is an autosomal recessive neuromuscular disorder characterized by progressive muscle weakness, associated with deletions of the survival motor neuron 1 (SMN1) gene. Approximately 94% of SMA patients carry homologous deletions of SMN1 exon(s) 7 (and 8). Because of the high incidence and severity of the disease, precise detection and quantification of SMN1 and SMN2 gene copy numbers is essential for diagnosis and genetic counseling. We have developed a reliable single-tube tetra-primer PCR assay to simultaneously detect both the SMN1 and SMN2 exon 7 deletion using the advantage of C/T difference at nucleotide position of 840 in exon 7. The assay has been optimized and tested in 48 healthy controls, 20 known patients with SMA, 12 carriers (one SMN1 copy), and 8 amniotic fluids suspected of having SMA for whom we had determined the SMN1/SMN2 deletion by an additional PCR-RFLP method. We have observed complete concordance between methods. Our tetra-primer PCR assay is sensitive, low-cost, and easy to use method for simultaneous detection of both SMN1 and SMN2 deletion, which could be used even in "low-tech" laboratories.
Mol Cell Probes 2010 Jun
PMID:Rapid diagnosis of spinal muscular atrophy using tetra-primer ARMS PCR assay: simultaneous detection of SMN1 and SMN2 deletion. 2002 60

Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder determined by functional impairment of alpha-motor neurons within the spinal cord. SMA is caused by functional loss of the survival motor neuron gene 1 (SMN1), whereas disease severity is mainly influenced by the number of SMN2 copies. SMN2, which produces only low levels of full-length mRNA/protein, can be modulated by small molecules and drugs, thus offering a unique possibility for SMA therapy. Here, we analysed suberoylanilide hydroxamic acid (SAHA), a FDA-approved histone deacetylase inhibitor, as potential drug in two severe SMA mouse models each carrying two SMN2 transgenes: US-SMA mice with one SMN2 per allele (Smn(-/-);SMN2(tg/tg)) and Taiwanese-SMA mice with two SMN2 per allele (Smn(-/-);SMN2(tg/wt)), both on pure FVB/N background. The US-SMA mice were embryonically lethal with heterozygous males showing significantly reduced fertility. SAHA treatment of pregnant mothers rescued the embryonic lethality giving rise to SMA offspring. By using a novel breeding strategy for the Taiwanese model (Smn(-/-);SMN2(tg/tg) x Smn(-/+) mice), we obtained 50% SMA offspring that survive approximately 10 days and 50% control carriers in each litter. Treatment with 25 mg/kg twice daily SAHA increased lifespan of SMA mice by 30%, significantly improved motor function abilities, reduced degeneration of motor neurons within the spinal cord and increased the size of neuromuscular junctions and muscle fibers compared with vehicle-treated SMA mice. SMN RNA and protein levels were significantly elevated in various tissues including spinal cord and muscle. Hence, SAHA, which lessens the progression of SMA, might be suitable for SMA therapy.
Hum Mol Genet 2010 Apr 15
PMID:SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy. 2009 77

The association of mitochondrial DNA mutation with type 2 diabetes mellitus (T2DM) is well established. In this study we aimed to assess the frequency of A3243G, A8296G, and other mitochondrial mutations with reference to clinical features in the diabetic population of Coimbatore, India. The study group included 150 patients (89 women and 61 men) with T2DM, whereas the control group included 100 nondiabetic people (59 women and 41 men). Genotyping was done by polymerase chain reaction followed by single-strand confirmation polymorphism method. A3243G and A8296G mutations were found to be prevalent in patients with T2DM when compared with the control group. The A3243G mutation was found in two patients, and both these patients showed similar clinical characteristics, thus representing a putative clinical subtype. A8296G mutation was detected in one patient. The same mutation was shared with his mother who was diagnosed to have diabetes mellitus (DM) with neuromuscular disorder. The siblings of the patient did not show any symptoms of DM. Lipid profile and urea and creatinine levels were found to be significantly high (10% and 0.064%) in patients with T2DM compared with control subjects. We concluded that the identification of these mitochondrial point mutations indicates a new genetic predisposition of DM in Coimbatore population.
Genet Test Mol Biomarkers 2010 Feb
PMID:Prevalence of mitochondrial tRNA gene mutations and their association with specific clinical phenotypes in patients with type 2 diabetes mellitus of Coimbatore. 2014 11

Spinal muscular atrophy (SMA) is the most common genetic disease leading to infant mortality. This neuromuscular disorder is caused by the loss or mutation of the telomeric copy of the 'survival of motor neuron' (Smn) gene, termed SMN1. Loss of SMN1 leads to reduced SMN protein levels, inducing degeneration of motor neurons (MN) and progressive muscle weakness and atrophy. To date, SMA remains incurable due to the lack of a method to deliver therapeutically active molecules to the spinal cord. Gene therapy, consisting of reintroducing SMN1 in MNs, is an attractive approach for SMA. Here we used postnatal day 1 systemic injection of self-complementary adeno-associated virus (scAAV9) vectors carrying a codon-optimized SMN1 sequence and a chimeric intron placed downstream of the strong phosphoglycerate kinase (PGK) promoter (SMNopti) to overexpress the human SMN protein in a mouse model of severe SMA. Survival analysis showed that this treatment rescued 100% of the mice, increasing life expectancy from 27 to over 340 days (median survival of 199 days) in mice that normally survive about 13 days. The systemic scAAV9 therapy mediated complete correction of motor function, prevented MN death and rescued the weight loss phenotype close to normal. This study reports the most efficient rescue of SMA mice to date after a single intravenous injection of an optimized SMN-encoding scAAV9, highlighting the considerable potential of this method for the treatment of human SMA.
Hum Mol Genet 2011 Feb 15
PMID:Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. 2111 96


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>