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Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity
Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Child Development Centers, Clalit Health Care Services, Israel.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Department of General Pediatrics, University of Münster, Münster, Germany.ORCID-id: 0000-0003-2305-9948
Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel.
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2022 (Engelska)Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 145, nr 3, s. 872-878Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.

Ort, förlag, år, upplaga, sidor
Oxford University Press, 2022. Vol. 145, nr 3, s. 872-878
Nyckelord [en]
amyotrophic lateral sclerosis, exome sequencing, SOD1, superoxide dismutase
Nationell ämneskategori
Neurologi Neurovetenskaper Medicinsk genetik
Identifikatorer
URN: urn:nbn:se:umu:diva-194841DOI: 10.1093/brain/awab416ISI: 000767441400001PubMedID: 34788402Scopus ID: 2-s2.0-85129780082OAI: oai:DiVA.org:umu-194841DiVA, id: diva2:1662729
Tillgänglig från: 2022-06-01 Skapad: 2022-06-01 Senast uppdaterad: 2022-06-01Bibliografiskt granskad

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Park, Julien H.Nordström, UlrikaMarklund, Stefan L.Andersen, Peter Munch

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Park, Julien H.Nordström, UlrikaMarklund, Stefan L.Andersen, Peter Munch
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