ArticleMolecular psychiatry2019
Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.
Article in Molecular psychiatry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- A novel missense variant at the site of interaction between RLIM and E2 ubiquitin-conjugating enzymes causes Tønne-Kalscheuer syndrome.BMC pediatrics · 2025Article
- Emerging roles for E3 ubiquitin ligases in neural development and disease.Frontiers in cell and developmental biology · 2025Review
- Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective.Journal of medical genetics · 2024Article
- Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses.Life science alliance · 2024Article
- Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders.FEBS letters · 2023Review
- Therapeutic validation and targeting of signalling networks that are dysregulated in intellectual disability.The FEBS journal · 2023Article
- The role of s-palmitoylation in neurological diseases: implication for zDHHC family.Frontiers in pharmacology · 2023Review
- Activity-based probe profiling of RNF12 E3 ubiquitin ligase function in Tonne-Kalscheuer syndrome.Life science alliance · 2022Article
- Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses.Genome medicine · 2022Article
- An RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations.Science signaling · 2022Article
- Ubiquitin ligases: guardians of mammalian development.Nature reviews. Molecular cell biology · 2022Review
- Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression.Journal of molecular cell biology · 2022Article
- Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation.Molecules (Basel, Switzerland) · 2021Review
- The Impact of X-Chromosome Inactivation on Phenotypic Expression of X-Linked Neurodevelopmental Disorders.Brain sciences · 2021Review
- A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome.Scientific reports · 2021Article
- Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling.Developmental cell · 2020Article
- RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features.American journal of human genetics · 2020Article
- Whole genome sequencing identifies a duplicated region encompassing Xq13.2q13.3 in a large Iranian family with intellectual disability.Molecular genetics & genomic medicine · 2020Article
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Authors and funding
45 authors at 17 institutions in 7 countries.
Funding
No grant is acknowledged in the PubMed record.
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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