Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in   superoxide dismutase gene: A possible new subtype of familial ALS

Akiyama, Masashi; Ogasawara, Masahito; Matsubara, Yoichi; Narisawa, Kuniaki; Nakamura, Shozo; Itoyama, Yasuto; Abe, Kōji

doi:10.1016/0022-510x(94)90097-3

Cited by 88 publications

(37 citation statements)

References 17 publications

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“…SOD H46RH48Q mice recapitulate human disease over a timecourse approximately twice the duration of SOD G93A mouse pathology, but display little or no human SOD enzymatic activity [ (Wang et al 2002)]. Both the SOD G93A and SOD H46RH48Q mutations have previously been linked to ALS disease in humans [ (Aoki et al 1994), (Enayat et al 1995), and (Gurney et al 1994)]. Additionally, as a negative control, mice which express wild-type human Cu/Zn SOD at levels comparable to those seen in the SOD G93A mice (SOD WT mice) were crossed onto the ARE-hPAP line and evaluated at the maximal timepoint assayed in the SOD G93A animals (110 days) to ensure that the presence of elevated human SOD, itself, wasn't the causative factor behind any observed changes [(Dal Canto and Gurney 1995)].…”

Section: Resultsmentioning

confidence: 99%

Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

Kraft

Resch

Johnson

et al. 2007

Experimental Neurology

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Oxidative stress plays a key role in the neuronal loss exhibited in amyotrophic lateral sclerosis (ALS), an event precipitating irreversible muscle atrophy. By crossing ALS mouse models (SOD G93A and SOD H46RH48Q ) with an antioxidant response element (ARE) reporter mouse, we identified activation characteristics of the ARE system throughout the timecourse of motor neuron disease. Surprisingly, the earliest and most significant activation of this genetic sensor of oxidative stress occurred in the distal muscles of mutant SOD mice. The resultant data supports existing hypotheses that the muscle is somehow implicated during the initial pathology of these mice. Subsequently, Nrf2-ARE activation appears to progress in a retrograde fashion along the motor pathway. These data provide timely information concerning the contributions of the Nrf2-ARE pathway in ALS disease progression.

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Section: Resultsmentioning

confidence: 99%

Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

Kraft

Resch

Johnson

et al. 2007

Experimental Neurology

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“…We have summarized SOD1 mutation cases with a disease duration of >20 years in Table 2. Patients harboring E22G, G37R, H46R, G93D, G93C, or I104F mutations exhibited generally mild clinical courses (11,(15)(16)(17)(18)(19)(20)(21). On the other hand, patients with I113T, L144F, and C111Y mutations exhibited intrafamilial phenotypic variation from rapid to slow progression.…”

Section: Discussionmentioning

confidence: 99%

Marked intrafamilial phenotypic variation in a family with SOD1 C111Y mutation

Nakamura¹,

Hineno²,

Yoshida³

et al. 2012

Amyotroph Lateral Scler

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Objectives: To identify the disease-causing mutation in and report on the clinical features of a Japanese family that had coexisting phenotypes of amyotrophic lateral sclerosis and spinal muscular atrophy. Methods: The family comprised 9 patients (6 men and 3 women). We reviewed their clinical records and performed mutation analysis of the copper/zinc superoxide dismutase (SOD1) gene in some of these patients. Results:The patients either had a rapid (n = 7) or an extremely long (n = 2) clinical course. The mean age at onset was 39.0 ± 13.7 years (range: 20-68 years). The initial symptoms were bulbar palsy (n = 2), upper (n = 4) or lower (n = 2) limb muscle weakness, or leg cramps (n = 1). The total disease duration varied widely, ranging from 1 year to >69 years. We identified a SOD1 C111Y mutation in the patients of this family. Conclusion: The family showed a marked intrafamilial phenotypic variation associated with the SOD1 C111Y mutation. Elucidating the biological basis of disease expression in patients with SOD1 C111Y mutation may provide us with useful information to develop therapeutic approaches and to prevent disease progression.

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“…The change in conformation of loop 50-59 upon dimerization is reflected also on the location of Cys57, which can or cannot perform a H-bond with the side chain of Arg143 depending on its conformation (see below). FALS mutations are spread over the entire molecule but a higher density of mutations are clustered in a few regions of the protein: at the interface between the two subunits (mainly in loop IV and b 8), in the odd loops and at the corresponding end of the b barrel, and in the even loops [52][53][54][55][56]. Some of the residues involved in FALS mutations are conserved in SOD structures from different species (Fig.…”

Section: Structure Constraints and Calculationsmentioning

confidence: 99%

The solution structure of reduced dimeric copper zinc superoxide dismutase. The structural effects of dimerization

Banci¹,

Bertini²,

Cramaro³

et al. 2002

Eur J Biochem

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The solution structure of homodimeric Cu 2 Zn 2 superoxide dismutase (SOD) of 306 aminoacids was determined on a 13 C, 15 N and 70% 2 H labeled sample. Two-thousand eighthundred and five meaningful NOEs were used, of which 96 intersubunit, and 115 dihedral angles provided a family of 30 conformers with an rmsd from the average of 0.78 ± 0.11 and 1.15 ± 0.09 Å for the backbone and heavy atoms, respectively. When the rmsd is calculated for each subunit, the values drop to 0.65 ± 0.09 and 1.08 ± 0.11 Å for the backbone and heavy atoms, respectively.The two subunits are identical on the NMR time scale, at variance with the X-ray structures that show structural differences between the two subunits as well as between different molecules in the unit cell. The elements of secondary structure, i.e. eight b sheets, are the same as in the X-ray structures and are well defined. The odd loops (I, III and V) are well resolved as well as loop II located at the subunit interface. On the contrary, loops IV and VI show some disorder. The residues of the active cavity are well defined whereas within the various subunits of the X-ray structure some are disordered or display different orientation in different X-ray structure determinations. The copper(I) ion and its ligands are well defined. This structure thus represents a well defined model in solution relevant for structure-function analysis of the protein. The comparison between the solution structure of monomeric mutants and the present structure shows that the subunit-subunit interactions increase the order in loop II. This has the consequences of inducing the structural and dynamic properties that are optimal for the enzymatic function of the wild-type enzyme. The regions 37-43 and 89-95, constituting loops III and V and the initial part of the b barrel and showing several mutations in familial amyotrophis lateral sclerosis (FALS)-related proteins have a quite extensive network of H-bonds that may account for their low mobility. Finally, the conformation of the key Arg143 residue is compared to that in the other dimeric and monomeric structures as well as in the recently reported structure of the CCS-superoxide dismutase (SOD) complex.

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Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in superoxide dismutase gene: A possible new subtype of familial ALS

Cited by 88 publications

References 17 publications

Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

Marked intrafamilial phenotypic variation in a family with SOD1 C111Y mutation

The solution structure of reduced dimeric copper zinc superoxide dismutase. The structural effects of dimerization

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