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Relevance to Autism

Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.

Molecular Function

A Rho-GTPase-activating protein involved in cell migration and outgrowth of axons and dendrites.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.
ASD
SCZ
Support
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.
ID, epilepsy/seizures
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ID
Support
A novel in-frame deletion affecting the BAR domain of OPHN1 in a family with intellectual disability and hippocampal alterations.
ID
Support
Characterization of intellectual disability and autism comorbidity through gene panel sequencing.
ID, ASD or autistic traits
Support
Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.
ASD
Support
Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.
ASD
Support
Expanding the phenotypic spectrum associated with OPHN1 variants.
Mental retardation, X-linked, with cerebellar hypo
DD, epilepsy/seizures
Support
Expanding the phenotypic spectrum associated with OPHN1 mutations: Report of 17 individuals with intellectual disability but no cerebellar hypoplasia.
ID
Epilepsy/seizures, behavioral abnormalities
Highly Cited
Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia.
CCH
Recent Recommendation
Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine imma...
Recent Recommendation
Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance.
ID
Recent Recommendation
The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors.
Recent Recommendation
The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1.
Recent Recommendation
Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN184R001 
 frameshift_variant 
 dupAAGAATTC 
  
 Familial 
 Maternal 
 Multi-generational 
 GEN184R002 
 stop_gained 
 c.184C>T 
 p.Gln62Ter 
 De novo 
 NA 
  
 GEN184R003 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN184R004 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN184R005 
 missense_variant 
 c.2114A>G 
 p.His705Arg 
 Familial 
 Maternal 
  
 GEN184R006 
 inframe_deletion 
 c.781_891del 
 del37 
 Familial 
 Maternal 
 Multi-generational 
 GEN184R007 
 missense_variant 
 c.2035G>A 
 p.Asp679Asn 
 Familial 
 Maternal 
  
 GEN184R008 
 missense_variant 
 c.746T>C 
 p.Leu249Pro 
 De novo 
 NA 
  
 GEN184R009 
 splice_site_variant 
 c.384+3A>C 
  
 Familial 
 Maternal 
 Multi-generational 
 GEN184R010 
 stop_gained 
 c.697C>T 
 p.Gln233Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN184R011 
 missense_variant 
 c.727C>T 
 p.Arg243Trp 
 Familial 
 Maternal 
 Multi-generational 
 GEN184R012 
 missense_variant 
 c.1235G>A 
 p.Gly412Asp 
 Unknown 
  
 Simplex 
 GEN184R013 
 missense_variant 
 c.590T>A 
 p.Val197Glu 
 De novo 
 NA 
  
 GEN184R014 
 frameshift_variant 
 c.549dup 
 p.Gln184SerfsTer23 
 De novo 
 NA 
  
 GEN184R015 
 missense_variant 
 c.2035G>A 
 p.Asp679Asn 
 Familial 
 Maternal 
  
 GEN184R016 
 frameshift_variant 
 c.931_932dup 
 p.Gln311HisfsTer7 
 De novo 
 NA 
 Simplex 
 GEN184R017 
 missense_variant 
 c.2323G>A 
 p.Val775Met 
 De novo 
 NA 
  

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
Duplication
 2
 
X
Deletion
 2
 
X
Duplication
 1
 
X
Deletion-Duplication
 10
 
X
Duplication
 2
 
X
Duplication
 2
 
X
Duplication
 1
 

Model Summary

Ophn1 controls the maturation of dendritic spines either by maintaining the density of mature spines or by limiting the extension of new filopodia.

References

Type
Title
Author, Year
Primary
Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine imma...

M_OPHN1_1_KO_HM

Model Type: Genetic
Model Genotype: Hemizygous
Mutation: Insertion of 100 bp in the coding sequence of exon 9, which leads to the premature STOP codon after the BAR domain (AA 1-242) and before the PH and GAP domains in the Ophn1 gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6(B6)
Genetic Background: Not Specified
ES Cell Line: SV129/Pas
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_OPHN1_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity1
Increased
Description: Increased levels of activity
Exp Paradigm: Male mice:actimeter, open field, dark-light box- light-dark exploration test
 Light-dark exploration test
 Unreported
Paw preference1
Decreased
Description: Decreased proportion of lateralized individuals in terms of paw preference
Exp Paradigm: Male mice: collins paradigm for paw preference
 Paw preference test
 5-7 months
General locomotor activity1
Increased
Description: Increased levels of activity
Exp Paradigm: Male mice:actimeter, open field, dark-light box-open field test
 Open field test
 Unreported
Dendritic architecture: spine density1
Decreased
Description: Decreased density of mushroom-shaped dendrites spines along apical dendrites of ca1 pyramidal neurons
Exp Paradigm: Male mice: golgi staining method analysis of ca1 pyramidal neurons
 Golgi-cox staining
 12 weeks
Brain anatomy1
Abnormal
Description: Abnormal dilation of lateral and third ventricles
Exp Paradigm: Male mice: cerebroventricular volume measurement by histological analysis
 Histology
 8-9 months, 3-4 weeks
Presynaptic function: paired-pulse facilitation1
Decreased
Description: Decreased paired-pulse faciliation of fepsp of schaffer-commissural afferents
Exp Paradigm: Male mice: paired-pulse stimulation
 Paired-pulse ratio
 6 weeks
Aggression1
Abnormal
Description: Abnormal behavior - increased snout sniffing of intruder
Exp Paradigm: Male mice: resident-intruder test
 Resident-intruder test
 Unreported
Spatial reference memory1
Decreased
Description: Decreased spatial reference learning and memory
Exp Paradigm: Male mice: morris water maze test
 Morris water maze test
 Unreported
Anxiety1
 No change
 Light-dark exploration test
 Unreported
Anxiety1
 No change
 Elevated zero maze test
 Unreported
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Unreported
Brain cytoarchitecture1
 No change
 Golgi-cox staining
 12 weeks
Brain morphology1
 No change
 Histology
 2.5-9 weeks
Brain size1
 No change
 Histology
 8-9 months
Dendritic architecture: spine density1
 No change
 Electron microscopy
 Unreported
Synaptic plasticity1
 No change
 Field potential recordings
 6 weeks
Olfaction1
 No change
 NA
 Unreported
Aggression1
 No change
 Resident-intruder test
 Unreported
Social memory1
 No change
 Social recognition test
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Molecular profile, Physiological parameters, Repetitive behavior, Seizure


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ARHGAP26 Rho GTPase activating protein 26 23092 Q9UNA1 IP; LC-MS/MS
Huttlin EL , et al. 2015
CDC42 cell division cycle 42 (GTP binding protein, 25kDa) 998 P60953 GTP hydrolysis assay
Billuart P , et al. 1998
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
HOMER1 homer homolog 1 (Drosophila) 9456 Q86YM7 GST
Nadif Kasri N , et al. 2011
RAC1 ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) 5879 P63000 GTP hydrolysis assay
Billuart P , et al. 1998
RHOA ras homolog gene family, member A 387 P61586 GTP hydrolysis assay
Billuart P , et al. 1998
Sh3gl2 SH3-domain GRB2-like 2 20404 Q62420 Y2H; GST; IP/WB
Nakano-Kobayashi A , et al. 2009
Gria1 glutamate receptor, ionotropic, AMPA 1 50592 P19490 IP/WB
Nadif Kasri N , et al. 2009
Gria2 glutamate receptor, ionotropic, AMPA 2 29627 P19491 IP/WB
Nadif Kasri N , et al. 2009

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