Subjects

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.

Author information

Author notes

  1. These authors contributed equally: Suzanna G.M. Frints, Aysegul Ozanturk.

  2. These authors jointly supervised this work: Christelle Golzio, Cristina Gontan, Vera M. Kalscheuer.

Affiliations

  1. Department of Clinical Genetics, Maastricht University Medical Center+, azM, Maastricht, 6202 AZ, The Netherlands

    • Suzanna G. M. Frints
    • , Kees E. P. van Roozendaal
    •  & Joep Geraedts
  2. Department of Genetics and Cell Biology, School for Oncology and Developmental Biology, GROW, FHML, Maastricht University, Maastricht, 6200 MD, The Netherlands

    • Suzanna G. M. Frints
    • , Kees E. P. van Roozendaal
    •  & Joep Geraedts
  3. Center for Human Disease Modeling and Departments of Pediatrics and Psychiatry, Duke University, Durham, NC, 27710, USA

    • Aysegul Ozanturk
    • , Sungjin Moon
    • , Nicholas Katsanis
    •  & Christelle Golzio
  4. Unidad de Genética Clínica, Hospital Virgen del Rocío, Sevilla, 41920, Spain

    • Germán Rodríguez Criado
  5. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, 72076, Germany

    • Ute Grasshoff
    • , Claudia Bauer
    • , Christopher Schroeder
    • , Andreas Dufke
    • , Olaf Riess
    •  & Peter Bauer
  6. Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, 3015 CN, Rotterdam, The Netherlands

    • Bas de Hoon
    • , Eveline Rentmeester
    • , Joost Gribnau
    •  & Cristina Gontan
  7. Department of Gynaecology and Obstetrics, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands

    • Bas de Hoon
  8. GOLD (Genetics of Learning and Disability) Service, Hunter Genetics, Waratah, NSW, 2298, Australia

    • Michael Field
    •  & Lucinda Murray
  9. Clinique de Génétique médicale Guy Fontaine, Centre de référence maladies rares Anomalies du développement Hôpital Jeanne de Flandre, Lille, 59000, France

    • Sylvie Manouvrier-Hanu
  10. EA 7364 RADEME Maladies Rares du Développement et du Métabolisme, Faculté de Médecine, Université de Lille, Lille, 59000, France

    • Sylvie Manouvrier-Hanu
  11. Division of Molecular & Human Genetics, Nationwide Children’s Hospital, Columbus, OH, 43205, USA

    • Scott E. Hickey
    •  & Theresa Mihalic Mosher
  12. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, 43205, USA

    • Scott E. Hickey
    • , Theresa Mihalic Mosher
    • , Peter White
    •  & Daniel C Koboldt
  13. Center for Human Genetics, University Hospitals Leuven, Leuven, 3000, Belgium

    • Molka Kammoun
    • , Jean-Pierre Fryns
    • , Joris Vermeesch
    •  & Koen Devriendt
  14. Alfred I. duPont Hospital for Children Nemours, Wilmington, DE, 19803, USA

    • Karen W. Gripp
  15. Service de Génétique, Hôpital Bretonneau, CHU de Tours, Tours, 37044, France

    • Annick Toutain
    •  & Martine Raynaud
  16. UMR 1253, iBrain, Université de Tours, Inserm, Tours, 37032, France

    • Annick Toutain
    •  & Martine Raynaud
  17. The Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, 43205, USA

    • Theresa Mihalic Mosher
    • , Benjamin J. Kelly
    • , Peter White
    •  & Daniel C Koboldt
  18. Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany

    • Hao Hu
    •  & Hans-Hilger Ropers
  19. Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany

    • Stefan A. Haas
  20. Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5000, Australia

    • Eric Haan
    • , Marie Shaw
    • , Renee Carroll
    •  & Jozef Gecz
  21. South Australian Clinical Genetics Service, SA Pathology (at Women’s and Children’s Hospital), North Adelaide, SA, 5006, Australia

    • Eric Haan
    •  & Jan Liebelt
  22. Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, 5006, Australia

    • Kathryn Friend
    •  & Lynne Hobson
  23. Centre for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), UZ Brussel, 1090, Brussels, Belgium

    • Marjan De Rademaeker
  24. South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia

    • Jozef Gecz
  25. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Translational Medicine and Neurogenetics; Centre National de la Recherche Scientifique, UMR7104; Institut National de la Santé et de la Recherche Médicale, U964, Université de Strasbourg, 67400, Illkirch, France

    • Christelle Golzio
  26. Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany

    • Vera M. Kalscheuer

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Suzanna G. M. Frints or Vera M. Kalscheuer.

Electronic supplementary material