Park JH1, Elpers C1, Reunert J1, McCormick ML2, Mohr J3, Biskup S3, Schwartz O1, Rust S1, Grüneberg M1, Seelhöfer A1, Schara U4, Boltshauser E5, Spitz DR2, Marquardt T1
Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•-) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis. In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity. The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype. These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease and should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis.
- Department of General Paediatrics, University of Münster, Münster, Germany.
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, USA.
- CeGaT GmbH und Praxis für Humangenetik Tübingen, Tübingen, Germany.
- Department of Paediatric Neurology, University Hospital Essen, Essen, Germany.
- Department of Paediatric Neurology, University Children’s Hospital, Zürich, Switzerland.