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

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 cosegregating 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.

Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling

“…Functional diversification of protein kinases is an important evolutionary tool, which employs preexisting signalling cassettes for regulation of increasingly complex cellular processes. (Bustos et al, 2018;Frints et al, 2018). Furthermore, phosphorylation of distal elements in the RING E3 c-CBL mediates enzymatic activation (Dou et al, 2013).…”

“…RNF12 mutations cause an X-linked neurodevelopmental disorder termed Tonne-Kalscheuer Syndrome (TOKAS) (Frints et al, 2018;Hu et al, 2016;Tonne et al, 2015), which is underpinned by impaired RNF12 E3 ubiquitin ligase activity resulting in deregulated neuronal differentiation (Bustos et al, 2018). Thus, we hypothesised that SRPK phosphorylates and regulates RNF12, which may represent functional diversification of SRPKs in developmental signalling.…”

“…Mutations in RNF12 cause a neurodevelopmental disorder termed Tonne-Kalscheuer Syndrome (TOKAS), which is a syndromic form of X-linked intellectual disability (Frints et al, 2018;Hu et al, 2016;Tonne et al, 2015). We showed previously that TOKAS mutations specifically impair RNF12…”

RLIM enhances BMP signalling mediated fetal lung development in mice

“…Mutations in RLIM have first been reported to cause X-linked intellectual disability and behavioral disorders [12,13]. Most recently, we have provided a detailed phenotypic description of 9 families with rare and likely pathogenic RLIM variants [14]. Next to the aforementioned phenotype, RLIM lesions are also associated with multiple congenital malformations which are dominated by congenital diaphragmatic hernia and lung hypoplasia, in addition to variable congenital heart defects, urogenital tract and skeletal abnormalities.…”

“…Next to the aforementioned phenotype, RLIM lesions are also associated with multiple congenital malformations which are dominated by congenital diaphragmatic hernia and lung hypoplasia, in addition to variable congenital heart defects, urogenital tract and skeletal abnormalities. These malformations are compatible with a dysregulation of BMP dependent signaling which is normally promoted by RLIM-mediated degradation of SMAD7 [5,14].…”