MED20 mutation associated with infantile basal ganglia degeneration and brain atrophy
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Infantile movement disorders are rare and genetically heterogeneous. We set out to identify the disease-causing mutation in siblings with a novel recessive neurodegenerative movement disorder. Genetic linkage analysis and whole-exome sequencing were performed in the original family. A cohort of six unrelated patients were sequenced for further mutations in the identified candidate gene. Pathogenicity of the mutation was evaluated by in silico analyses and by structural modeling. We identified the first and homozygous mutation (p.Gly114Ala) in the Mediator subunit 20 gene (MED20) in siblings presenting with infantile-onset spasticity and childhood-onset dystonia, progressive basal ganglia degeneration, and brain atrophy. Mediator refers to an evolutionarily conserved multi-subunit RNA polymerase II co-regulatory complex. Pathogenicity of the identified missense mutation is suggested by in silico analyses, by structural modeling, and by previous reporting of mutations in four distinct Mediator subunits causing neurodegenerative phenotypes. No further MED20 mutations were detected in this study.
Conclusion: We delineate a novel infantile-onset neurodegenerative movement disorder and emphasize the Mediator complex as critical for normal neuronal function. Definitive proof of pathogenicity of the identified MED20 mutation will require confirmation in unrelated patients.
KeywordsDystonia Infantile neurodegeneration Exome sequencing Basal ganglia degeneration Mediator complex
Mediator subunit 20 gene
Magnetic resonance imaging
Neurodegeneration with brain iron accumulation
National Center for Biotechnology Information
Nucleoporin 62 kDa gene
Polymerase chain reaction
Protein Data Bank
- PolyPhen 2
Polymorphism Phenotyping version 2
Sorting Intolerant from Tolerant
Single nucleotide polymorphism
The authors thank Sabine Möstl (Medical University of Vienna) for video documentation and Dr. Malvina Herceg (Medical University of Vienna) for performing NCV. The study was partially funded by the Austrian Society of Pediatrics (ÖGKJ) and an in-house grant of the Department of Pediatrics and Adolescent Medicine of Medical University Vienna (both to J.V.).
The Austrian Society of Pediatrics had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.
Conflict of interest
The authors declare no competing financial interests.
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