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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Acknowledgements
The authors would like to thank the individuals and their families who participated in this study. We thank Jackie Boyle for her contribution to Family C, Friederike Ruebenstrunk for establishing contact with Family I, and Joop Lavel for technical assistance. The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. This study was supported by two Dutch NWO VENI grants: OND1312421 to S.G.M.F. and OND1358237 to C.G.P, the European Union grant QLG3-CT-2002-01810 (EuroMRX Consortium), the EU FP7 project GENCODYS, grant number 241995, Australian NHMRC grants 1091593 and 1041920 to J.G., and the European Commission via its Erasmus Joint Doctoral programme 2013-0040 to M.K. C.G. is a grantee of a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation.
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Frints, S.G.M., Ozanturk, A., Rodríguez Criado, G. et al. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder. Mol Psychiatry 24, 1748–1768 (2019). https://doi.org/10.1038/s41380-018-0065-x
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DOI: https://doi.org/10.1038/s41380-018-0065-x
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