1. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder
- Author
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Kees E. P. van Roozendaal, Molka Kammoun, Michael Field, Andreas Dufke, Joris Vermeesch, Annick Toutain, Hao Hu, Theresa Mihalic Mosher, Joep P.M. Geraedts, Hans-Hilger Ropers, Peter White, Jan Liebelt, Sungjin Moon, Vera M. Kalscheuer, Joost Gribnau, Bas de Hoon, Germán Rodríguez Criado, Marie Shaw, Ute Grasshoff, Stefan A. Haas, Benjamin J. Kelly, Lynne Hobson, Marjan De Rademaeker, Christelle Golzio, Suzanna G.M. Frints, Olaf Riess, Claudia S. Bauer, Eric Haan, Nicholas Katsanis, Peter Bauer, Karen W. Gripp, Renee Carroll, Jozef Gecz, Jean Pierre Fryns, Cristina Gontan, Aysegul Ozanturk, Eveline Rentmeester, Martine Raynaud, Scott E. Hickey, Daniel C. Koboldt, Sylvie Manouvrier-Hanu, Lucinda Murray, Koen Devriendt, Christopher Schroeder, Kathryn Friend, Developmental Biology, Obstetrics & Gynecology, MUMC+: DA KG Bedrijfsbureau (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Duke University [Durham], Hospital Universitario Virgen del Rocío [Sevilla], University of Tübingen, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hunter Genetics, Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Nationwide Children's Hospital, Ohio State University [Columbus] (OSU), University Hospitals Leuven [Leuven], Nemours/Alfred I. du Pont Hospital for Children, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, University of Adelaide, Women’s and Children’s Hospital [Adelaide], SA Pathology [Adelaide, SA, Australia], Vrije Universiteit Brussel (VUB), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte, Reproduction and Genetics, Clinical sciences, and Medical Genetics
- Subjects
Male ,0301 basic medicine ,X-linked intellectual disability ,PROTEIN ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,FUNCTIONAL-ACTIVITY ,Mice ,0302 clinical medicine ,Genes, X-Linked ,X Chromosome Inactivation ,RNF12 ,Missense mutation ,TRANSCRIPTION ,Child ,Zebrafish ,Genetics ,Middle Aged ,Phenotype ,Pedigree ,Ubiquitin ligase ,Psychiatry and Mental health ,medicine.anatomical_structure ,Child, Preschool ,Female ,Adult ,Conduct Disorder ,Adolescent ,Ubiquitin-Protein Ligases ,NPAS3 ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Intellectual Disability ,medicine ,Ring finger ,Animals ,Humans ,Molecular Biology ,Transcription factor ,RLIM ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,CHROMOSOME INACTIVATION ,MUTATIONS ,Infant, Newborn ,Ubiquitination ,Wild type ,Zebrafish Proteins ,medicine.disease ,biology.organism_classification ,HEK293 Cells ,030104 developmental biology ,Mutation ,Mental Retardation, X-Linked ,biology.protein ,LIM COFACTORS ,030217 neurology & neurosurgery ,Transcription Factors ,GENE UBE2A CAUSE - 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.
- Published
- 2019
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