Journal ArticleDOI
Compound heterozygous D90A and D96N SOD1 mutations in a recessive amyotrophic lateral sclerosis family
Collette K. Hand,Veronique Mayeux-Portas,Jawad Khoris,Valerie Briolotti,Pierre Clavelou,William Camu,Guy A. Rouleau +6 more
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TLDR
A French amyotrophic lateral sclerosis family with two distinct mutations in the Cu/Zn superoxide dismutase (SOD1) gene is described and it is proposed that in this family both mutations are required for the development of disease.Abstract:
We describe a French amyotrophic lateral sclerosis (ALS) family with two distinct mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The D90A mutation has been well described and clearly shown to cause recessive ALS. In this family, affected individuals are heterozygous for the D90A mutation and also carry a single copy of a novel SOD1 mutation, D96N. We propose that in this family both mutations are required for the development of disease.read more
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Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders.
Byron Caughey,Peter T. Lansbury +1 more
TL;DR: Recent biophysical studies aimed at elucidating the precise mechanism of in vitro aggregation and animal modeling studies support the emerging notion that an ordered prefibrillar oligomer, or protofibril, may be responsible for cell death and that the fibril form that is typically observed at autopsy may actually be neuroprotective.
Journal ArticleDOI
A century-old debate on protein aggregation and neurodegeneration enters the clinic
TL;DR: Drug candidates that inhibit aggregation have the potential to slow the progression of Alzheimer's disease, Parkinson's disease and related disorders and could, if administered presymptomatically, drastically reduce the incidence of these diseases.
Journal ArticleDOI
Clinical genetics of amyotrophic lateral sclerosis: what do we really know?
TL;DR: The only clinical feature that distinguishes recognized hereditary from apparently sporadic ALS is a lower mean age of onset in the former, and all the clinical features reported in hereditary cases have also been observed in sporadic cases.
Journal ArticleDOI
Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS.
TL;DR: mounting evidence from mice with cell restrictive, repressible or chimeric expression of mutant SOD1 transgenes and bone marrow transplants supports non-neuronal origins of neuroprotection in ALS.
Journal ArticleDOI
Genetics of motor neuron disorders: new insights into pathogenic mechanisms
TL;DR: The functional classes of MND genes identified so far are likely to aid the selection of high-priority candidate genes for future investigation, including those for so-called sporadic cases.
References
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Journal ArticleDOI
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Journal ArticleDOI
Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase
Han Xiang Deng,Afif Hentati,John A. Tainer,Zafar Iqbal,Annarueber Cayabyab,Wu Yen Hung,Elizabeth D. Getzoff,Ping Hu,Brian Herzfeldt,Raymond P. Roos,Carolyn Warner,Gang Deng,Edwin Soriano,Celestine Smyth,Hans E. Parge,Aftab Ahmed,Allen D. Roses,Robert A. Hallewell,Margaret A. Pericak-Vance,Teepu Siddique +19 more
TL;DR: In this article, single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis.
Journal ArticleDOI
Amyotrophic lateral sclerosis: Recent insights from genetics and transgenic mice
TL;DR: The evidence that this disease arises from oxidative and excitotoxic injury to critical subcellular targets in motor neurons is considered, and current hypotheses concerning the mechanism of motor neuron death in ALS are summarized.
Journal ArticleDOI
Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.
Peter M. Andersen,Peter Nilsson,Veli Ala-Hurula,Marja-Leena Keränen,Ilkka Tarvainen,Tuula Haltia,Lotta Nilsson,Michael Binzer,Lars Forsgren,Stefan L. Marklund +9 more
TL;DR: Heterozygosity for an exon 4 mutation, Asp90Ala, is reported in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland, suggesting that this CuZn–SOD mutation causes ALS by a gain of function rather than by loss, and that the Asp 90Ala mutation is less detrimental than previously reported mutations.
Journal ArticleDOI
Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia.
Peter M. Andersen,Peter Nilsson,M L Keränen,Lars Forsgren,J Hägglund,M Karlsborg,L O Ronnevi,Ole Gredal,Stefan L. Marklund +8 more
TL;DR: The results suggest that patients with mutations in the CuZn-superoxide dismutase gene constitute one disease entity, and that the Val14Gly and Asp76Tyr mutations have not been reported before, and the latter is the first mutation to be found in exon 3 of the Cu Zn- superoxide dismUTase gene.