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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. (2018). Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder. Molecular Psychiatry, 2018. doi:10.1038/s41380-018-0065-x.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-4C60-E Version Permalink: http://hdl.handle.net/21.11116/0000-0002-5992-5
Genre: Journal Article

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Frints, Suzanna G. M. , Author
Ozanturk, Aysegul , Author
Rodríguez Criado, Germán , Author
Grasshoff, Ute, Author
de Hoon, Bas, Author
Field, Michael, Author
Manouvrier-Hanu, Sylvie , Author
Hickey, Scott E. , Author
Kammoun, Molka , Author
Gripp, Karen W. , Author
Bauer, Claudia, Author
Schroeder, Christopher , Author
Toutain, Annick , Author
Mihalic Mosher, Theresa , Author
Kelly, Benjamin J. , Author
White, Peter, Author
Dufke, Andreas, Author
Rentmeester, Eveline , Author
Moon, Sungjin, Author
Koboldt, Daniel C. , Author
van Roozendaal, Kees E. P. , AuthorHu, Hao, AuthorHaas, Stefan A.1, Author              Ropers, Hans-Hilger2, Author              Murray, Lucinda , AuthorHaan, Eric, AuthorShaw, Marie, AuthorCarroll, Renee , AuthorFriend, Kathryn , AuthorLiebelt, Jan, AuthorHobson, Lynne , AuthorDe Rademaeker, Marjan , AuthorGeraedts, Joep , AuthorFryns, Jean-Pierre , AuthorVermeesch, Joris , AuthorRaynaud, Martine , AuthorRiess, Olaf, AuthorGribnau, Joost , AuthorKatsanis, Nicholas , AuthorDevriendt, Koen , AuthorBauer, Peter, AuthorGecz, Jozef , AuthorGolzio, Christelle , AuthorGontan, Cristina , AuthorKalscheuer, Vera M.3, Author               more..
Affiliations:
1Sequencing and Genomics (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              
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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 Abstract: 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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Language(s): eng - English
 Dates: 2018-02-282018-05-04
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/s41380-018-0065-x
PMID: 29728705
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Title: Molecular Psychiatry
Source Genre: Journal
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Publ. Info: Houndmills, Hampshire, UK : Stockton Press
Pages: - Volume / Issue: 2018 Sequence Number: - Start / End Page: - Identifier: ISSN: 1359-4184 (print) 1476-5578 (online)
CoNE: /journals/resource/954925619131