Cu/Zn superoxide dismutase gene mutations in amyotrophic lateral sclerosis: correlation between genotype and clinical features.

Radunović, Aleksandar; Leigh, P. Nigel

doi:10.1136/jnnp.61.6.565

Cited by 138 publications

(79 citation statements)

References 67 publications

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“…Thus, it is not surprising that we find such small differences versus wild-type enzyme in reactivity and binding of the Cu ions and the stability of the molecule. Still, the mutant enzyme is linked strongly to ALS, and is indeed, next to Ala4Val, the most common CuZn-SOD mutation found in ALS patients (Radunovic and Leigh, 1996). If the CuZn-SOD mutations linked to ALS cause the disease by essentially the same mechanism, which we think is the most likely proposition, there should be a least common denominator applying to all of them.…”

Section: Discussionmentioning

confidence: 91%

Normal Binding and Reactivity of Copper in Mutant Superoxide Dismutase Isolated from Amyotrophic Lateral Sclerosis Patients

Marklund¹,

Andersen

Forsgren

et al. 1997

Journal of Neurochemistry

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Abstract:In some families with amyotrophic lateral sclerosis (ALS), the disease is linked to mutations in the gene encoding CuZn-superoxide dismutase. The mutant CuZn-superoxide dismutases appear to cause motor neuron degeneration by a toxic property, suggested to be linked to an altered reactivity of the active-site Cu ions. Asp 90Ala mutant CuZn-superoxide dismutase was isolated from six patients with ALS, allowing properties of the mutant enzyme synthesized and conditioned in patients with ALS to be examined. The molecular mass of the Asp 90Ala mutant CuZn-superoxide dismutase was 45 Da lower than that of the wild-type enzyme, as expected from the amino acid exchange. The mobility after sodium dodecyl sulfate-polyacrylamide gel electrophoresis was markedly increased, however, suggesting altered properties of the polypeptide. The mutant CuZnsuperoxide dismutase showed a minimal reduction in stability but did not differ significantly from the wild-type enzyme in enzymic activity, in content and affinity for active-site Cu ions and in the propensity to catalyze formation of hydroxyl radicals. Our findings suggest that the deleterious effect of mutant CuZn-superoxide dismutases on motor neurons in ALS is not related to altered reactivity of active-site Cu ions, resulting in increased oxidant stress. Attention should therefore also be directed at other mechanisms and properties of the mutant polypeptides and their degradation products. Key Words: Superoxide dismutase-Copper-StabilityHydroxyl radicals-Amyotrophic lateral sclerosis. J. Neurochem. 69, 675-681 (1997).of the >50 different mutations reported, the inheritance is dominant and there are significant reductions in the CuZn-SOD activity in erythrocytes Ogasawara et al., 1993;Robberecht et al., 1994), various cell types (Borchelt et al., 1994;Tsuda et al., 1994;Pramatarova et al., 1995), and CNS tissue (Bowling et aI., 1993).With one mutation, Asp90Ala (D9OA), ALS is mostly found in homozygous individuals (Andersen et al., 1995(Andersen et al., , 1996, although a few heterozygous cases have also been described (Andersen et al., 1995;Robberecht et al., 1996). The SOD activity in erythrocytes from these patients is essentially normal (Andersen et al., 1995). Furthermore, transgenic overexpression of CuZn-SOD carrying three different ALS-linked mutations has been shown to cause motor neuron disease in mice (Gurney et al., 1994;Ripps et al., 1995;Wong et al., 1995). In these mice, there was increased (Gurney et al., 1994;Wong et al., 1995) or unaltered (Ripps et al., 1995) total CuZn-SOD activity in the CNS. Finally, mice lacking CuZn-SOD showed no evidence of motor neuron degeneration (Reaume et al., 1996). These findings suggest that the various mutations cause ALS by a deleterious interaction with motor neuron constituents, rather than by loss of function. Supporting this hypothesis, it has been shown that ALS-linked mutations change the CuZn-SOD from an anti-to a proapoptotic factor when overexpressed in neuronal Amyotrophic lateral sclerosis (ALS) is a devast...

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Section: Discussionmentioning

confidence: 91%

Normal Binding and Reactivity of Copper in Mutant Superoxide Dismutase Isolated from Amyotrophic Lateral Sclerosis Patients

Marklund¹,

Andersen

Forsgren

et al. 1997

Journal of Neurochemistry

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“…Considering that this type of MND is recessively inherited, truncation-specific loss of function of alsin is assumed to contribute to selective disappearance of motor neurons in ALS. On the contrary, almost all SOD1 mutants have amino acid substitutions, and furthermore, some mutants maintain their original function as a scavenger of free radicals (24). They are therefore considered to cause ALS by gain of toxic function.…”

Section: Expression Of Sod1 Mutants Induces Death Of Motor Neuronal Cmentioning

confidence: 99%

Alsin, the Product of ALS2 Gene, Suppresses SOD1 Mutant Neurotoxicity through RhoGEF Domain by Interacting with SOD1 Mutants

Kanekura¹,

Hashimoto²,

Niikura³

et al. 2004

Journal of Biological Chemistry

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Mutation of the ALS2 gene encoding alsin is linked to the onset of autosomal recessive motor neuron diseases, including juvenile-onset amyotrophic lateral sclerosis (ALS). Alsin long form (LF) belongs to the family of the guanine nucleotide exchanging factor (GEF) for small GTPases. Expression of alsin LF, but not alsin short form, protected motor neuronal cells from toxicity induced by mutants of the Cu/Zn-superoxide dismutase (SOD1) gene, which cause autosomal dominant ALS. In contrast, expression of alsin did not suppress neurotoxicity by other neurodegenerative insults such as Alzheimer's disease-related genes. Deletion analysis of alsin LF demonstrated that the RhoGEF domain is essential for alsin-mediated neuroprotection. Furthermore, we found that alsin LF bound to SOD1 mutants, but not to wtSOD1, via the RhoGEF domain. Such functional and physical interaction between two ALS-related genes will become a promising clue to clarify the pathogenesis of ALS and other motor neuron diseases.

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“…3 In SALS cases, mutations have only rarely been found. 4 In the initial study of the involvement of the SOD1 gene in FALS, two Belgian families were included with the L38V and G93C mutations respectively (families 11 and 57 in Rosen et al 2 ). We here present a survey of nine additional Belgian ALS families.…”

Section: Introductionmentioning

confidence: 99%

Mutational analysis of the Cu/Zn superoxide dismutase gene in 23 familial and 69 sporadic cases of amyotrophic lateral sclerosis in Belgium

et al. 1999

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder caused by degeneration of motor neurons of the spinal cord and brain. The majority of ALS cases are sporadic (SALS). However, in 10-15% of ALS cases the disease is inherited as an autosomal dominant trait (familial ALS or FALS). We used a non-radioactive SSCP method, in combination with solid phase sequencing, to screen the entire SOD1 (Cu/Zn superoxide dismutase) coding region and flanking intronic sequences for mutations. Twenty-three patients from 11 ALS families and 69 SALS patients of Belgian origin were studied. Three different mutations were identified (L38V, D90A and G93C) in seven families. Importantly, the D90A was only found in the heterozygous state. In addition two single base pair variants (IVS1 + 19G > A and AAC139 AAT) were identified in two SALS patients. These results suggest that the SOD1 analysis is useful in FALS but less so in SALS cases. The SSCP analysis has proved fast and reliable for this purpose.

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Cu/Zn superoxide dismutase gene mutations in amyotrophic lateral sclerosis: correlation between genotype and clinical features.

Cited by 138 publications

References 67 publications

Normal Binding and Reactivity of Copper in Mutant Superoxide Dismutase Isolated from Amyotrophic Lateral Sclerosis Patients

Normal Binding and Reactivity of Copper in Mutant Superoxide Dismutase Isolated from Amyotrophic Lateral Sclerosis Patients

Alsin, the Product of ALS2 Gene, Suppresses SOD1 Mutant Neurotoxicity through RhoGEF Domain by Interacting with SOD1 Mutants

Mutational analysis of the Cu/Zn superoxide dismutase gene in 23 familial and 69 sporadic cases of amyotrophic lateral sclerosis in Belgium

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