Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/123183
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dc.contributor.authorFrints, S.en
dc.contributor.authorOzanturk, A.en
dc.contributor.authorRodríguez Criado, G.en
dc.contributor.authorGrasshoff, U.en
dc.contributor.authorde Hoon, B.en
dc.contributor.authorField, M.en
dc.contributor.authorManouvrier-Hanu, S.en
dc.contributor.authorE Hickey, S.en
dc.contributor.authorKammoun, M.en
dc.contributor.authorGripp, K.en
dc.contributor.authorBauer, C.en
dc.contributor.authorSchroeder, C.en
dc.contributor.authorToutain, A.en
dc.contributor.authorMihalic Mosher, T.en
dc.contributor.authorKelly, B.en
dc.contributor.authorWhite, P.en
dc.contributor.authorDufke, A.en
dc.contributor.authorRentmeester, E.en
dc.contributor.authorMoon, S.en
dc.contributor.authorKoboldt, D.en
dc.contributor.authoret al.en
dc.date.issued2018en
dc.identifier.citationMolecular Psychiatry, 2018; 24(11):1748-1768en
dc.identifier.issn1359-4184en
dc.identifier.issn1476-5578en
dc.identifier.urihttp://hdl.handle.net/2440/123183-
dc.descriptionPublished online: 4 May 2018en
dc.description.abstractRLIM, 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.en
dc.description.statementofresponsibilitySuzanna G. M. Frints ... Eric Haan, Marie Shaw, Renee Carroll, Kathryn Friend, Jan Liebelt, Lynne Hobson ... Jozef Gecz ... et al.en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rights© Macmillan Publishers Limited, part of Springer Nature 2018en
dc.titlePathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorderen
dc.typeJournal articleen
dc.identifier.rmid0030086660en
dc.identifier.doi10.1038/s41380-018-0065-xen
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1091593en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1041920en
dc.identifier.pubid419161-
pubs.library.collectionPaediatrics publicationsen
pubs.library.teamDS03en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidHaan, E. [0000-0002-7310-5124]en
dc.identifier.orcidShaw, M. [0000-0002-5060-190X]en
dc.identifier.orcidCarroll, R. [0000-0002-6979-3710]en
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
Appears in Collections:Paediatrics publications

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