Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: A decade of discoveries, defects and disputes
ABSTRACT Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations.
Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations.
One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease-associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S591, V87A, T88deltaTAD, A89T, V97M, S105deltaSL, V118L, D124G, G141X, G147R, 11515) were found, bringing the total number of SOD1 gene mutations in ALS to 105.
Mutations in the SOD1 gene are found both in sporadic and familial ALS cases without any definite predilection for any part of the gene. A common structural denominator for the 16 novel mutations or previously reported mutations is not obvious. Similarly, the nature of the putative acquired toxic function of mutant SOD1 remains unresolved. We conclude that patients with SOD1 mutations may infrequently show symptoms and signs unrelated to the motor systems, sometimes obscuring the diagnosis of ALS.
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- "The only clinically available therapy to date is riluzole (Rilutek), which marginally extends survival by limiting excitotoxicity  and increasing neurotrophin release from astrocytes . The majority of ALS cases are sporadic, whereas only 10% are familial (FALS) , among which 15-20% can be traced to point mutations in cytosolic Cu 2+ /Zn 2+ superoxide dismutase 1 (SOD1) . "
ABSTRACT: We here propose an updated concept of stem cells (SCs), with an emphasis on neural stem cells (NSCs). The conventional view, which has touched principally on the essential property of lineage multipotency (e.g., the ability of NSCs to differentiate into all neural cells), should be broadened to include the emerging recognition of biofunctional multipotency of SCs to mediate systemic homeostasis, evidenced in NSCs in particular by the secretion of neurotrophic factors. Under this new conceptual context and taking the NSC as a leading example, one may begin to appreciate and seek the "logic" behind the wide range of molecular tactics the NSC appears to serve at successive developmental stages as it integrates into and prepares, modifies, and guides the surrounding CNS micro- and macro-environment towards the formation and self-maintenance of a functioning adult nervous system. We suggest that embracing this view of the "multipotency" of the SCs is pivotal for correctly, efficiently, and optimally exploiting stem cell biology for therapeutic applications, including reconstitution of a dysfunctional CNS.DNA research: an international journal for rapid publication of reports on genes and genomes 12/2011; 9(4):574-85. DOI:10.2174/157015911798376299 · 2.35 Impact Factor
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- "About 10% of all ALS cases are familial (FALS), meaning that they are caused by inherited genetic damage known as mutations    . Inheritance of damage to the enzyme CuZn superoxide dismutase (SOD1) is involved in about 20% of FALS   . Earlier work has provided evidence that (1) mutations impair the stability of SOD1 molecules so that they fall apart, and (2) that the pieces of the molecule then clump together or stick to other molecules in the neuron, creating obstructions to normal processes . "
ABSTRACT: Approximately 10% of Amyotrophic lateral sclerosis/ Motor Neuron Disease (ALS/MND) is inherited of which up to 20% is caused bymutations, (changes) in the superoxide dismutase 1 (SOD1) gene. Detailed bioinformatics study of all the known mutations in the SOD1 gene revealed interesting information. The information about allthe experimentally proven mutations in the SOD1 gene was collected and analyzed using bioinformatics tools and software programs. Wecomputationally tried to find out whether the presence of microsatellite plot in the SOD1 gene has any significance in the generation of these mutations. Our analysis revealed that we found 13microsatellites out of which 7 microsatellites regions have found to be mutated and have fallen inside domain region. The mutation falling in the domain region seems to be inducting a change in the secondary structure and resulting in change or absence of protein function. Thus indicating a positive role of microsatellites in mutagenesis.
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- "ns. While the majority of ALS cases are sporadic in nature, a small percentage (~10%) has a familial component. Although the cause of sporadic ALS remains unclear, a clear genetic link to point mutations in the cytosolic Cu 2+ /Zn 2+ superoxide dismutase 1 (SOD1) has been shown in a small group of familial ALS (FALS) patients (Rosen et. al., 1993; Andersen et. al., 2003). This has led to the generation of transgenic mice and rats over-expressing multiple copies of mutant SOD1 (SOD1 G93A ) that have many of the characteristics of both the familial and sporadic form of human disease (Gurney et. al., 1994; Hall et. al., 1998; Howland et. al., 2002). The exact etiology of ALS is still mystery, but recent o"
ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons within the brain and spinal cord are lost, leading to paralysis and death. Recently, a correlation between head trauma and the incidence of ALS has been reported. Furthermore, new invasive neurosurgical studies are being planned which involve inserting needles directly to the spinal cord. We therefore tested whether acute trauma to the spinal cord via a knife wound injury would lead to accelerated disease progression in rodent models of ALS (SOD1(G93A) rats). A longitudinal stab injury using a small knife was performed within the lumbar spinal cord region of presymptomatic SOD1(G93A) rats. Host glial activation was detected in the lumbar area surrounding a micro-knife lesion at 2 weeks after surgery in both wild type and SOD1(G93A) animals. However, there was no sign of motor neuron loss in the injured spinal cord of any animal and normal motor function was maintained in the ipsilateral limb. These results indicate that motor neurons in presymptomatic G93A animals are not affected by an invasive puncture wound injury involving reactive astrocytes. Furthermore, acute trauma alone does not accelerate disease onset or progression in this ALS model which is important for future strategies of gene and cell therapies directly targeting the spinal cord of ALS patients.Experimental Neurology 12/2009; 221(2):346-52. DOI:10.1016/j.expneurol.2009.12.004 · 4.62 Impact Factor