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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 möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Rnf213 ; Exome Sequencing ; Leigh Syndrome ; Moyamoya ; Stroke; Moyamoya-disease; Features
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 26, Heft: 2, Seiten: , Artikelnummer: 101013 Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Baltimore, Md.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
G-503292-001
Förderungen 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
DOI 10.1016/j.gim.2023.101013
WOS ID 001194984300001
Scopus ID 85180612748
PubMed ID 37924258
Erfassungsdatum 2023-11-28
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