Phenotype in an Infant with
            <i>SOD1</i>
            Homozygous Truncating Mutation

Benatar, Michael; Nordström, Ulrika; Tsiakas, Konstantinos; Johannsen, Jessika; Volk, Alexander E; Bierhals, Tatjana; Zetterström, Per; Marklund, Stefan L.; Hempel, Maja; Santer, René

doi:10.1056/nejmc1905039

Cited by 41 publications

(36 citation statements)

References 5 publications

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“…Indeed, homozygous and even heterozygous knockout of the Sod1 gene in mice exhibited a wide range of phenotypes relevant to ALS such as slowly progressive motor deficits [8]. Recently, furthermore, human patients with a homozygous truncating variant c.335dupG (p.C112Wfs*11) in the SOD1 gene that leads to total absence of the enzymatic activity were reported, and the resulting phenotype was marked by progressive loss of motor abilities [9,10]. Heterozygous carriers of the c.335dupG variant had an approximately halved SOD1 activity when compared to normal controls but appear not to develop symptoms of ALS [10].…”

Section: Misfolded Forms Of Sod1 As a Pathological Hallmark Of Sod1-alsmentioning

confidence: 99%

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Furukawa

Tokuda

2020

Transl Neurodegener

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Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons. Increasing numbers of genes are found to be associated with ALS; among those, the first identified gene, SOD1 coding a Cu/Zn-superoxide dismutase protein (SOD1), has been regarded as the gold standard in the research on a pathomechanism of ALS. Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1 (SOD1-ALS). Nonetheless, involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations (non-SOD1 ALS), which occupies more than 90% of total ALS cases. In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins; therefore, SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases, non-SOD1 ALS. In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo, we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.

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Section: Misfolded Forms Of Sod1 As a Pathological Hallmark Of Sod1-alsmentioning

confidence: 99%

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Furukawa

Tokuda

2020

Transl Neurodegener

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“…Atrophy, fasciculations, and other signs of lower motor neuron involvement were not noted. Her parents, both heterozygous for the mutation were healthy at the time of the report while the level of SOD1 activity was half that of the normal level 28 . Another report of the same homozygous truncating variant c.335dupG (p.Cys112Trpfs*11) in SOD1 was identified in another patient with tetraspasticity.…”

Section: Discussionmentioning

confidence: 97%

Premature termination codons in SOD1 causing Amyotrophic Lateral Sclerosis are predicted to escape the nonsense-mediated mRNA decay

Guissart

Mouzat

Kantar

et al. 2020

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is the most common and severe adult-onset motoneuron disease and has currently no effective therapy. Approximately 20% of familial ALS cases are caused by dominantly-inherited mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), which represents one of the most frequent genetic cause of ALS. Despite the overwhelming majority of ALS-causing missense mutations in SOD1, a minority of premature termination codons (PTCs) have been identified. mRNA harboring PTCs are known to be rapidly degraded by nonsense-mediated mRNA decay (NMD), which limits the production of truncated proteins. The rules of NMD surveillance varying with PTC location in mRNA, we analyzed the localization of PTCs in SOD1 mRNA to evaluate whether or not those PTCs can be triggered to degradation by the NMD pathway. Our study shows that all pathogenic PTCs described in SOD1 so far can theoretically escape the NMD, resulting in the production of truncated protein. This finding supports the hypothesis that haploinsufficiency is not an underlying mechanism of SOD1 mutant-associated ALS and suggests that PTCs found in the regions that trigger NMD are not pathogenic. Such a consideration is particularly important since the availability of SOD1 antisense strategies, in view of variant treatment assignment.

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“…In contrast, there is only a small number of congenital diseases that are caused by abnormalities in the detoxification systems of chemical compounds that induce DNA damage (tier 1). Recent clinical reports have shown that a complete absence of the superoxide dismutase 1 (SOD1) enzyme, which is involved in the removal of ROS, causes an extreme oxygen sensitivity in patient's cells and is associated with autosomal recessive progressive spastic tetraplegia and axial hypotonia (STAHP), characterized by severe and progressive psychomotor retardation in humans (46,47). Note that mutations in the SOD1 gene usually cause autosomal dominant amyotrophic lateral sclerosis because of the toxic effects of protein aggregation rather than by the loss of enzymatic activity (48).…”

Section: Discussionmentioning

confidence: 99%

Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

et al. 2020

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Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5−/−Aldh2E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

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Phenotype in an Infant with SOD1 Homozygous Truncating Mutation

Cited by 41 publications

References 5 publications

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Premature termination codons in SOD1 causing Amyotrophic Lateral Sclerosis are predicted to escape the nonsense-mediated mRNA decay

Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

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