RT Journal Article
T1 Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.
A1 Frints, Suzanna G M
A1 Ozanturk, Aysegul
A1 Rodríguez Criado, Germán
A1 Grasshoff, Ute
A1 de Hoon, Bas
A1 Field, Michael
A1 Manouvrier-Hanu, Sylvie
A1 E Hickey, Scott
A1 Kammoun, Molka
A1 Gripp, Karen W
A1 Bauer, Claudia
A1 Schroeder, Christopher
A1 Toutain, Annick
A1 Mihalic Mosher, Theresa
A1 Kelly, Benjamin J
A1 White, Peter
A1 Dufke, Andreas
A1 Rentmeester, Eveline
A1 Moon, Sungjin
A1 Koboldt, Daniel C
A1 van Roozendaal, Kees E P
A1 Hu, Hao
A1 Haas, Stefan A
A1 Ropers, Hans-Hilger
A1 Murray, Lucinda
A1 Haan, Eric
A1 Shaw, Marie
A1 Carroll, Renee
A1 Friend, Kathryn
A1 Liebelt, Jan
A1 Hobson, Lynne
A1 De Rademaeker, Marjan
A1 Geraedts, Joep
A1 Fryns, Jean-Pierre
A1 Vermeesch, Joris
A1 Raynaud, Martine
A1 Riess, Olaf
A1 Gribnau, Joost
A1 Katsanis, Nicholas
A1 Devriendt, Koen
A1 Bauer, Peter
A1 Gecz, Jozef
A1 Golzio, Christelle
A1 Gontan, Cristina
A1 Kalscheuer, Vera M
AB 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.
YR 2018
FD 2018-05-04
LK http://hdl.handle.net/10668/12425
UL http://hdl.handle.net/10668/12425
LA en
DS RISalud
RD Apr 9, 2025