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  Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Frints, S. G. M., Ozanturk, A., Rodríguez Criado, G., Grasshoff, U., de Hoon, B., Field, M., et al. (2019). Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder. Molecular Psychiatry, 24(11), 1748-1768. doi:10.1038/s41380-018-0065-x.

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Frints_2018.pdf (Verlagsversion), 4MB
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© 2018 Springer Nature Limited
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Frints, Suzanna G. M. , Autor
Ozanturk, Aysegul , Autor
Rodríguez Criado, Germán , Autor
Grasshoff, Ute, Autor
de Hoon, Bas, Autor
Field, Michael, Autor
Manouvrier-Hanu, Sylvie , Autor
Hickey, Scott E. , Autor
Kammoun, Molka , Autor
Gripp, Karen W. , Autor
Bauer, Claudia, Autor
Schroeder, Christopher , Autor
Toutain, Annick , Autor
Mihalic Mosher, Theresa , Autor
Kelly, Benjamin J. , Autor
White, Peter, Autor
Dufke, Andreas, Autor
Rentmeester, Eveline , Autor
Moon, Sungjin, Autor
Koboldt, Daniel C. , Autor
van Roozendaal, Kees E. P. , AutorHu, Hao, AutorHaas, Stefan A.1, Autor           Ropers, Hans H.2, Autor           Murray, Lucinda , AutorHaan, Eric, AutorShaw, Marie, AutorCarroll, Renee , AutorFriend, Kathryn , AutorLiebelt, Jan, AutorHobson, Lynne , AutorDe Rademaeker, Marjan , AutorGeraedts, Joep , AutorFryns, Jean-Pierre , AutorVermeesch, Joris , AutorRaynaud, Martine , AutorRiess, Olaf, AutorGribnau, Joost , AutorKatsanis, Nicholas , AutorDevriendt, Koen , AutorBauer, Peter, AutorGecz, Jozef , AutorGolzio, Christelle , AutorGontan, Cristina , AutorKalscheuer, Vera M.3, Autor            mehr..
Affiliations:
1Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
2Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              
3Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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 Zusammenfassung: RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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Sprache(n): eng - English
 Datum: 2018-02-282018-05-042019-11
 Publikationsstatus: Erschienen
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 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: DOI: 10.1038/s41380-018-0065-x
PMID: 29728705
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Titel: Molecular Psychiatry
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Houndmills, Hampshire, UK : Stockton Press
Seiten: 21 Band / Heft: 24 (11) Artikelnummer: - Start- / Endseite: 1748 - 1768 Identifikator: ISSN: 1359-4184 (print) 1476-5578 (online)
CoNE: https://pure.mpg.de/cone/journals/resource/954925619131