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Brunet, T.* ; Zott, B.* ; Lieftüchter, V.* ; Lenz, D.* ; Schmidt, A.* ; Peters, P.* ; Kopajtich, R. ; Zaddach, M.* ; Zimmermann, H.* ; Hüning, I.* ; Ballhausen, D.* ; Staufner, C.* ; Bianzano, A.* ; Hughes, J.* ; Taylor, R.W.* ; McFarland, R.* ; Devlin, A.* ; Mihaljevic, M.* ; Barišić, N.* ; Rohlfs, M.* ; Wilfling, S.* ; Sondheimer, N.* ; Hewson, S.* ; Marinakis, N.M.* ; Kosma, K.* ; Traeger-Synodinos, J.* ; Elbracht, M.* ; Begemann, M.* ; Trepels-Kottek, S.* ; Hasan, D.* ; Scala, M.* ; Capra, V.* ; Zara, F.* ; van der Ven, A.T.* ; Driemeyer, J.* ; Apitz, C.* ; Kramer, J.* ; Strong, A.* ; Hakonarson, H.* ; Watson, D.* ; Mayr, J.A.* ; Prokisch, H. ; Meitinger, T.* ; Borggraefe, I.* ; Spiegler, J.* ; Baric, I.* ; Paolini, M.* ; Gerstl, L.* ; Wagner, M.

De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.

Genet. Med. 26:101013 (2023)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease (MMD). Case reports have also implicated specific variants in RNF213 with an early-onset form of MMD with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. METHODS: Patients were identified through reanalysis of exome sequencing (ES) data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient derived fibroblasts. RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the RING domain. Individuals presented either with early-onset stroke (n=11) or with Leigh syndrome (n=3). No genotype-phenotype correlation could be established. Proteomics using patient derived fibroblasts revealed no significant differences between clinical subgroups. 3D-modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting Zinc-binding suggesting a gain-of-function or dominant negative effect. CONCLUSIONS: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting Zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Rnf213 ; Exome Sequencing ; Leigh Syndrome ; Moyamoya ; Stroke; Moyamoya-disease; Features
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Journal Genetics in Medicine
Quellenangaben Volume: 26, Issue: 2, Pages: , Article Number: 101013 Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Baltimore, Md.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants Austrian Science Funds (FWF)
German Liver Foundation
European Joint Programme on Rare Diseases
Wellcome Centre for Mitochondrial Research
Mitochondrial Disease Patient Cohort (United Kingdom)
Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease
Medical Research Council
UK NIHR Biomedical Research Centre for Ageing and Age-related disease award
UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
MitoFoundation
Pathological Society
PerMiM Personalized Mitochondrial Medicine
EJP-RD project GENOMIT
K08 Mentored Career Development Award
Dietmar HoppFoundation, St. Leon-Rot, Germany