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

Suzanna G. M. Frints*, Aysegul Ozanturk, German Rodriguez Criado, Ute Grasshoff, Bas de Hoon, Michael Field, Sylvie Manouvrier-Hanu, Scott E. Hickey, Molka Kammoun, Karen W. Gripp, Claudia Bauer, Christopher Schroeder, Annick Toutain, Theresa Mihalic Mosher, Benjamin J. Kelly, Peter White, Andreas Dufke, Eveline Rentmeester, Sungjin Moon, Daniel C. KoboldtKees E. P. van Roozendaal, Hao Hu, Stefan A. Haas, Hans-Hilger Ropers, Lucinda Murray, Eric Haan, Marie Shaw, Renee Carroll, Kathryn Friend, Jan Liebelt, Lynne Hobson, Marjan De Rademaeker, Joep Geraedts, Jean-Pierre Fryns, Joris Vermeesch, Martine Raynaud, Olaf Riess, Joost Gribnau, Nicholas Katsanis, Koen Devriendt, Peter Bauer, Jozef Gecz, Christelle Golzio, Cristina Gontan, Vera M. Kalscheuer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)1748-1768
Number of pages21
JournalMolecular Psychiatry
Volume24
Issue number11
DOIs
Publication statusPublished - Nov 2019

Keywords

  • GENE UBE2A CAUSE
  • CHROMOSOME INACTIVATION
  • FUNCTIONAL-ACTIVITY
  • LIM COFACTORS
  • MUTATIONS
  • PROTEIN
  • RNF12
  • RLIM
  • NPAS3
  • TRANSCRIPTION

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