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Relevance to Autism

A rare missense variant in the RLIM gene (c.1067A>G; p.Tyr356Cys) segregated with disease in a three-generation Norwegian family with a novel X-linked intellectual disability syndrome characterized by autism, subtle facial dysmorphism, and severe feeding problems (Tonne et al., 2015).

Molecular Function

The protein encoded by this gene is a E3 ubiquitin protein ligase that targets LIM domain binding 1 (LDB1/CLIM) for proteasome-dependent degradation1. This protein and LDB1 are co-repressors of LHX1/LIM-1, a homeodomain transcription factor. By targeting ZFP42 for degradation, RLIM acts as an activator of random inactivation of X chromosome in the embryo.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Syndromic X-linked intellectual disability segregating with a missense variant in RLIM.
ASD, ID
Recent Recommendation
RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features
ID
ASD/autistic features
Recent Recommendation
RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation.
Recent Recommendation
Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.
Recent Recommendation
X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
ID

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN708R001 
 missense_variant 
 c.1067A>G 
 p.Tyr356Cys 
 Familial 
 Maternal 
 Multi-generational 
 GEN708R002 
 missense_variant 
 c.1760C>G 
 p.Pro587Arg 
 Familial 
 Maternal 
 Multi-generational 
 GEN708R003 
 missense_variant 
 c.1159C>T 
 p.Arg387Cys 
 Familial 
 Maternal 
 Multi-generational 
 GEN708R004 
 missense_variant 
 c.1795C>T 
 p.Arg599Cys 
 Familial 
 Maternal 
 Multi-generational 
 GEN708R005 
 missense_variant 
 c.230C>T 
 p.Pro77Leu 
 Familial 
 Maternal 
 Simplex 
 GEN708R006 
 missense_variant 
 c.1093C>T 
 p.Arg365Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN708R007 
 missense_variant 
 c.1729T>C 
 p.Tyr577His 
 Familial 
 Maternal 
 Multi-generational 
 GEN708R008 
 missense_variant 
 c.1792G>A 
 p.Asp598Asn 
 Familial 
 Maternal 
 Multi-generational 
 GEN708R009 
 missense_variant 
 c.1831C>T 
 p.Arg611Cys 
 Familial 
 Maternal 
 Extended multiplex 
 GEN708R010 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN708R011 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Multi-generational 
 GEN708R012 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN708R013 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN708R014 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN708R015 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN708R016 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Extended multiplex 
 GEN708R017 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Extended multiplex 
 GEN708R018 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Multiplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 
X
Deletion
 2
 
X
Duplication
 2
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Duplication
 8
 
X
Duplication
 5
 
X
Duplication
 1
 

Model Summary

Knockdown of rlim by morpholino or knockout by CRISPR results in significantly reduced head size in zebrafish larvae. This phenotype is rescued by wild type human RLIM mRNA as well as a benigh variant but not human RLIM mRNA carrying patient-specific misssense changes.

References

Type
Title
Author, Year
Primary
Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.

Z_RLIM_1_KD_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Zebrafish larvae at one- to two-cell stage were injected with 2ng splice-blocking morpholino against the third exonintron junction of rlim.
Allele Type: Loss-of-function
Strain of Origin: Unreported
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source:

Z_RLIM_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: F0 population of CRISPR-mutant rlim zebrafish embryos was generated by introducing small indels in the zebrafish ortholog of rlim using CRISPR/Cas9 genome editing approach.
Allele Type: Loss-of-function
Strain of Origin: Unreported
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source:

Z_RLIM_1_KD_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Brain size1
Decreased
Description: rlim zebrafish morphants showed a significant reduction of the head size (i.e., microcephaly) compared to controls.
 Microscopic analysis
 5 dpf
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

Z_RLIM_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Brain size1
Decreased
Description: rlim zebrafish morphants showed a significant reduction of the head size (i.e., microcephaly) compared to controls.
 Microscopic analysis
 5 dpf
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

 

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