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https://hdl.handle.net/2440/123183
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Type: | Journal article |
Title: | Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder |
Author: | Frints, S.G.M. Ozanturk, A. Rodríguez Criado, G. Grasshoff, U. de Hoon, B. Field, M. Manouvrier-Hanu, S. E Hickey, S. Kammoun, M. Gripp, K.W. Bauer, C. Schroeder, C. Toutain, A. Mihalic Mosher, T. Kelly, B.J. White, P. Dufke, A. Rentmeester, E. Moon, S. Koboldt, D.C. et al. |
Citation: | Molecular Psychiatry, 2018; 24(11):1748-1768 |
Publisher: | Springer Nature |
Issue Date: | 2018 |
ISSN: | 1359-4184 1476-5578 |
Statement of Responsibility: | Suzanna G. M. Frints ... Eric Haan, Marie Shaw, Renee Carroll, Kathryn Friend, Jan Liebelt, Lynne Hobson ... Jozef Gecz ... et al. |
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. |
Keywords: | Animals Zebrafish Humans Mice Mental Retardation, X-Linked Ubiquitin-Protein Ligases Zebrafish Proteins Transcription Factors Pedigree Conduct Disorder Mutation Adolescent Adult Middle Aged Child Child, Preschool Infant, Newborn Female Male X Chromosome Inactivation Genes, X-Linked Ubiquitination HEK293 Cells Intellectual Disability |
Description: | Published online: 4 May 2018 |
Rights: | © Macmillan Publishers Limited, part of Springer Nature 2018 |
DOI: | 10.1038/s41380-018-0065-x |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1091593 http://purl.org/au-research/grants/nhmrc/1041920 |
Published version: | http://dx.doi.org/10.1038/s41380-018-0065-x |
Appears in Collections: | Aurora harvest 8 Paediatrics publications |
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