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Relevance to Autism

A small subset of patients with Coffin-Lowry syndrome have also presented with autism (Zeniou et al., 2002) or transient autistic behavior (Manouvrier-Hanu et al., 1999), implicating RPS6KA3 as a syndromic ASD gene. On a related note, an ASD case had previously been identified who had also been given a provisional diagnosis of Coffin-Lowry syndrome (Bryson et al., 1988). More recently, a de novo loss-of-function variant in the RPS6KA3 gene was identified in an ASD case from the Simons Simplex Collection (O'Roak et al., 2012).

Molecular Function

This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Mutations in this gene are associated with Coffin-Lowry syndrome (CLS) [MIM:303600], a X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders, as well as with mental retardation, X-linked 19 (MRX19) [MIM:300844], a non-syndromic form of mild-to-moderate mental retardation.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
ASD
Support
High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.
Coffin-Lowry syndrome
ID
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Unknown diagnosis
Support
An Xp22.12 microduplication including RPS6KA3 identified in a family with variably affected intellectual and behavioral disabilities.
ID
Epilepsy, ADHD, PDD
Support
Unusual splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin-Lowry syndrome.
Coffin-Lowry syndrome
Support
Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities
White matter abnormalities
DD
Support
Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome.
Coffin-Lowry syndrome
ID, ASD
Support
First report of a Canadian epidemiological study of autistic syndromes.
ASD
CLS
Support
Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.
ASD
Highly Cited
A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation.
Coffin-Lowry syndrome

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN591R001 
 stop_gained 
 c.1106C>G 
 p.Ser369Ter 
 De novo 
 NA 
 Simplex 
 GEN591R002 
 missense_variant 
 c.566T>A 
 p.Ile189Lys 
 Familial 
 Maternal 
 Multiplex 
 GEN591R003 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN591R004 
 splice_site_variant 
 c.244-7A>G 
  
 De novo 
 NA 
 Unknown 
 GEN591R005 
 stop_gained 
 c.256A>T 
 p.Lys86Ter 
 De novo 
 NA 
  
 GEN591R006 
 intergenic_variant 
 G>T 
  
  
  
 Unknown 
 GEN591R007 
 splice_site_variant 
 c.632-2A>C 
  
 Familial 
 Maternal 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion-Duplication
 12
 
X
Deletion
 1
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Deletion
 2
 
X
Deletion
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 

Model Summary

RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS.

References

Type
Title
Author, Year
Primary
Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lo...

M_RPS6KA3_1_KO

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Homologous recombination mediated disruption of exon 2 of Rsk2 gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: 129 x 1/SvJ x C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: 129 x 1/SvJ
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_RPS6KA3_1_KO

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Synaptic morphology1
Abnormal
Description: Increased length of psds in non-perforated synapses, non-significant increase in psd length in perforated synapses, compared to wild type
Exp Paradigm: Quantiatative electron microscopy of axospinous asymmetric synapse
 Electron microscopy
 NA
Dendritic architecture: spine density1
Abnormal
Description: Increase in mean spine neck width, compared to wild type
Exp Paradigm: Quantiatative electron microscopy of axospinous asymmetric synapse
 Electron microscopy
 NA
Synaptic transmission1
Decreased
Description: Decreased synaptic tranmission in dentate gyrus indicated by reduction in fepsp slope across stimulus intensities
Exp Paradigm: In vivo field potential recordings at medial perforant path (mpp)-to-dentate granule cell synapse
 In vivo local field potential (lfp) recordings
 NA
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Decreased
Description: Decreased nmda/ampa ratio compared to wild type
Exp Paradigm: Field potential recordings: epsp, by proximal stimulation of the perforant path in dentate gyrus slices
 Field potential recordings
 NA
Presynaptic function: paired-pulse facilitation1
Decreased
Description: Amplitude of spike facilitation at long inter-stimulus intervals peaked at 100 ms for both knockouts and wildtypes, but was significantly decreased in knockouts compared to wild types
Exp Paradigm: In vivo field potential recordings at medial perforant path (mpp)-to-dentate granule cell synapse, stimulus intensity above threshold for evoking a population spike
 In vivo local field potential (lfp) recordings
 NA
Synaptic transmission1
Decreased
Description: Decreased synaptic tranmission in dentate gyrus indicated by reduction in fepsp slope at intensities higher than 15v
Exp Paradigm: Field potential recordings: slope of epsp by range of stimulus (input/ output relationship), , by proximal stimulation of the perforant path in dentate gyrus slices
 Field potential recordings
 NA
Cued or contextual fear conditioning: trace fear conditioning1
Decreased
Description: Decreased long-term retention of trace fear memory indicated by less freezing in response to conditioned tone-cs
Exp Paradigm: Fear conditioning test: trace
 Fear conditioning test
 NA
Cued or contextual fear conditioning: memory of context1
Abnormal
Description: Strong trend for increased extinction after re-exposure compared to wild type, decreased freezing compared to non re-exposed knockouts, while wild types did not show decreased freezing under same conditions
Exp Paradigm: Fear conditioning test: extinction, of contextual memory after re-exporsure at 24 h for 10 min, tested at 48 h (5 min)
 Fear conditioning test
 NA
Protein expression level evidence1
Decreased
Description: Decreased level of shank3 in dentate gyrus after induction of ltp, and non-significant decrease in basal level, compared to wild type
Exp Paradigm: Shank3 protein level after ltp induction
 Western blot
 NA
Regulation of gene expression1
Decreased
Description: Decreased level of egr1 after induction of ltp compared to wild type
Exp Paradigm: Egr1 protein level 3 h after ltp induction
 Western blot
 NA
Protein phosphorylation1
Decreased
Description: Decreased level of phosphorylated creb after induction of ltp, compared to wild type
Exp Paradigm: Creb s133 phosphorylation level 15 min after ltp induction
 Western blot
 NA
Cued or contextual fear conditioning: memory of context1
 No change
 Fear conditioning test
 NA
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 NA
Protein expression level evidence1
 No change
 Western blot
 NA
Protein expression level evidence1
 No change
 Western blot
 NA
Protein phosphorylation1
 No change
 Western blot
 NA
Brain morphology1
 No change
 Electron microscopy
 NA
Synapse density1
 No change
 Electron microscopy
 NA
Presynaptic function: paired-pulse facilitation1
 No change
 In vivo local field potential (lfp) recordings
 NA
Synaptic plasticity1
 No change
 In vivo local field potential (lfp) recordings
 NA
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

 

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