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Relevance to Autism

OTUD7A resides within the locus for 15q13.3 microdeletion syndrome (OMIM 612001). A recurrent 680 kb deletion affecting OTUD7A and CHRNA7 was identified in ten individuals from four unrelated families presenting with neurodevelopmental phenotypes including developmental delay, intellectual disability, and seizures (Shinawi et al., 2009). Two reports published in 2018 further implicated OTUD7A as a major contributor to the phenotypes observed in individuals with 15q13.3 microdeletion syndrome. Uddin et al., 2018 demonstrated that expression of wild-type OTUD7A in cortical neurons from a mouse model of 15q13.3 microdeletion syndrome [Df(h15q13)/+] rescued dendritic spine defects, whereas OTUD7A containing a de novo in-frame deletion variant that was identified in an ASD proband failed to do so. Yin et al., 2018 reported that OTUD7A knockout mice recapitulated many of the the phenotypes observed in Df(h15q13)-/- mice, including developmental delay, abnormal electroencephalography patterns and seizures, rediced ultrasonic vocalizations, impaired motor learning and motor coordination, and reduced acoustic startle.

Molecular Function

The protein encoded by this gene is a deubiquitinizing enzyme with deubiquitinating activity towards 'Lys-11'-linked polyubiquitin chains, as well as a possible tumor suppressor. The encoded protein acts on TNF receptor associated factor 6 (TRAF6) to control nuclear factor kappa B expression.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome.
ASD
Support
Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.
ASD
Support
A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes.
DD, ID, epilepsy/seizures
Recent Recommendation
Otud7a Knockout Mice Recapitulate Many Neurological Features of 15q13.3 Microdeletion Syndrome.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1005R001 
 inframe_deletion 
 c.1474_1482del 
 p.Asn492_Lys494del 
 De novo 
 NA 
 Multiplex 
 GEN1005R002 
 frameshift_variant 
 c.2214_2223del 
 p.Ala739ArgfsTer238 
 De novo 
 NA 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
15
Duplication
 10
  construct
15
Duplication
 1
 
15
Duplication
 2
 
15
Deletion
 1
 
15
Duplication
 66
  construct
15
Duplication
 14
 
15
Duplication
 3
 
15
Deletion-Duplication
 13
 
15
Deletion
 18
 
15
Deletion-Duplication
 43
 
15
Deletion-Duplication
 71
  construct

Model Summary

Otud7a-null mice show reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalizations, decreased grip strength, impaired motor learning/motor coordination, reduced acoustic startle, decreased spine density and reduced frequency of miniature excitatory postsynaptic currents (mEPSCs) in the frontal cortex compared to their wild-type littermates (Yin J, Am J Hu Genet, 2018).

References

Type
Title
Author, Year
Primary
Otud7a Knockout Mice Recapitulate Many Neurological Features of 15q13.3 Microdeletion Syndrome.

M_OTUD7A_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: C57BL/6J female mice were superovulated and mated with C57BL/6J males, and fertilized eggs were collected from the oviduct. The pronuclear-stage eggs at 1-cell stage were injected with Cas9 and sgRNAs targeting exon 4 to 6 of OTUD7A. The eggs were cultivated in kSOM overnight and then transferred into the oviducts of pseudopregnant FVB females. Heterozygous founders from CRISPR/Cas9 microinjection were backcrossed to wild-type mice (C57BL/6J) for two generations to obtain heterozygous mice for breeding pairs. The two sgRNAs deleted most of the OTU deubiquitinase domain, which created a premature stop codon in exon 8. .
Allele Type: knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not reported
Mutant ES Cell Line: Not reported
Model Source: 29395075; Jackson Laboratory JAX#031294.

M_OTUD7A_1_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: C57BL/6J female mice were superovulated and mated with C57BL/6J males, and fertilized eggs were collected from the oviduct. The pronuclear-stage eggs at 1-cell stage were injected with Cas9 and sgRNAs targeting exon 4 to 6 of OTUD7A. The eggs were cultivated in kSOM overnight and then transferred into the oviducts of pseudopregnant FVB females. Heterozygous founders from CRISPR/Cas9 microinjection were backcrossed to wild-type mice (C57BL/6J) for two generations to obtain heterozygous mice for breeding pairs. The two sgRNAs deleted most of the OTU deubiquitinase domain, which created a premature stop codon in exon 8. .
Allele Type: knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not reported
Mutant ES Cell Line: Not reported
Model Source: 29395075; Jackson Laboratory JAX#031294.

M_OTUD7A_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Grip strength1
Decreased
Description: Female mutants show decreased grip strength compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes.
 Grip strength test
 6.25 months
Negative geotaxis1
Decreased
Description: Mutants show delay in the development of reflexive negative geotaxis compared to controls.
Exp Paradigm: NA
 Negative geotaxis test
 0-2 weeks
Motor learning1
Decreased
Description: Mutants show decrease in latency to fall from a rotarod over successive trials, compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes.
 Accelerating rotarod test
 2.75 months
Motor coordination and balance1
Decreased
Description: Mutants show decrease in latency to fall from a rotarod compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes.
 Accelerating rotarod test
 2.75 months
Dendritic architecture: spine density1
Decreased
Description: Mutants show decreased number of dendritic spines in the frontal cortex and motor cortex but not in the somatosensory cortex, compared to controls.
Exp Paradigm: NA
 Golgi-cox staining
 4 weeks
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Otud7a-null mice display significantly reduced mepsc frequency in frontal cortices compared to controls.
Exp Paradigm: Pyramidal neurons in layer 2/3 regions of the frontal cortex were clamped.
 Whole-cell patch clamp
 1-2.75 months
Seizures1
Increased
Description: Mutants show abnormal repetitive-spike events compared to controls. the epileptiform activities were more prominent in the frontal cortex than the parietal cortex.
Exp Paradigm: Video-electroencephalography (eeg) and electromyography (emg) was recorded in freely moving mice.
 Electroencephalogram/electromyogram (eeg/emg)
 4 months
Sensorimotor gating1
Decreased
Description: Mutants show deficits in prepulse inhibibition compared to controls. female otud7a homozygous null mice showed reduced prepulse inhibition at 82 db prepulse intensity, compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes. prepulse intensities were 74, 78, and 82 db.
 Prepulse inhibition
 3.25 months
Vision1
Decreased
Description: Mutants show delay in the development of cliff avoidance reflex compared to controls.
Exp Paradigm: To evaluate cliff aversion pups were placed with their legs just within the edge of a paper box. the day when the pup avoided falling off the edge was recorded.
 Cliff avoidance test
 0-2 weeks
Startle response: acoustic stimulus1
Decreased
Description: Mutants show reduced startle response amplitude to acoustic stimulus compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes. prepulse intensities were 74, 78, and 82 db.
 Acoustic startle reflex test
 3.25 months
Ultrasonic vocalization: isolation induced1
Decreased
Description: Mutant mice had an impairment in an otud7a dosage-dependent manner, which was significant on days 6, 8, and 10, compared to controls.
Exp Paradigm: NA
 Monitoring ultrasonic vocalizations
 P2, 4, 6, 8, 10, 0-1.5 weeks
Developmental trajectory1
Decreased
Description: Mutants presented a significant preweaning growth delay compared to controls. mutants show a significant delay in incisor eruption and incisor growth compared to controls. mutants show no change in eye and ear opening developmental milestones compared to controls.
Exp Paradigm: The day of appearance of developmental landmarks - negative geotaxis, cliff aversion, incisor eruption and growth, eye lid opening, and ear opening - was recorded.
 Developmental milestone measurements
 0-2 weeks
Size/growth1
Decreased
Description: Mutants showed 30% reduction in body weight compared to heterozygotes and wildtype controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes.
 Body weight measurement
 0.5, 1, 2, 3 weeks
Anxiety1
Decreased
Description: Mutants spent more time in the open arms of the elevated plus maze compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes.
 Elevated plus maze test
 2.5 months
Cued or contextual fear conditioning: memory of cue1
Increased
Description: Mutants show increased freezing in response to conditioned cue compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes.
 Fear conditioning test
 3.25 months
Anxiety1
 No change
 Open field test
 2.5 months
Anxiety1
 No change
 Light-dark exploration test
 2.5 months
Depression1
 No change
 Forced swim test
 3 months
Cued or contextual fear conditioning: memory of context1
 No change
 Fear conditioning test
 3.25 months
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 3.25 months
Object recognition memory1
 No change
 Novel object recognition test
 6.75 months
General locomotor activity: ambulatory activity1
 No change
 Open field test
 2.5 months
Grip strength1
 No change
 Grip strength test
 6.25 months
Dendritic architecture: spine density1
 No change
 Golgi-cox staining
 4 weeks
Miniature post synaptic current amplitude: excitatory1
 No change
 Whole-cell patch clamp
 1-2.75 months
Repetitive nose pokes1
 No change
 Hole-board test
 2.5 months
Self grooming: perseveration1
 No change
 Grooming behavior assessments
 2.5 months
Hearing1
 No change
 Auditory brainstem response test
 3 months
Nest building behavior1
 No change
 Nest building assay
 3.5 months
Social approach1
 No change
 Three-chamber social approach test
 3 months
Social memory1
 No change
 Partition test
 3 months
 Not Reported: Circadian sleep/wake cycle, Immune response, Maternal behavior, Molecular profile, Physiological parameters

M_OTUD7A_1_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Self grooming: perseveration1
Decreased
Description: Mutants males show decrease in self grooming compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes.
 Grooming behavior assessments
 2.5 months
Startle response: acoustic stimulus1
Decreased
Description: Mutants show reduced startle response amplitude to acoustic stimulus compared to controls.
Exp Paradigm: Experiment was performed during the light cycle. experimenter remained blind to the genotypes. prepulse intensities were 74, 78, and 82 db.
 Acoustic startle reflex test
 3.25 months
Ultrasonic vocalization: isolation induced1
Decreased
Description: Mutant mice had an impairment in an otud7a dosage-dependent manner, which was significant on days 6, 8, and 10, compared to controls.
Exp Paradigm: NA
 Monitoring ultrasonic vocalizations
 P2, 4, 6, 8, 10, 0-1.5 weeks
Developmental trajectory1
 No change
 Developmental milestone measurements
 0-2 weeks
Size/growth1
 No change
 Body weight measurement
 0.5, 1, 2, 3 weeks
Anxiety1
 No change
 Open field test
 2.5 months
Anxiety1
 No change
 Light-dark exploration test
 2.5 months
Anxiety1
 No change
 Elevated plus maze test
 2.5 months
Depression1
 No change
 Forced swim test
 3 months
Cued or contextual fear conditioning: memory of context1
 No change
 Fear conditioning test
 3.25 months
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 3.25 months
Object recognition memory1
 No change
 Novel object recognition test
 6.75 months
General locomotor activity: ambulatory activity1
 No change
 Open field test
 2.5 months
Grip strength1
 No change
 Grip strength test
 6.25 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 2.75 months
Motor learning1
 No change
 Accelerating rotarod test
 2.75 months
Negative geotaxis1
 No change
 Negative geotaxis test
 0-2 weeks
Repetitive nose pokes1
 No change
 Hole-board test
 2.5 months
Self grooming: perseveration1
 No change
 Grooming behavior assessments
 2.5 months
Hearing1
 No change
 Auditory brainstem response test
 3 months
Sensorimotor gating1
 No change
 Prepulse inhibition
 3.25 months
Vision1
 No change
 Cliff avoidance test
 0-2 weeks
Nest building behavior1
 No change
 Nest building assay
 3.5 months
Social approach1
 No change
 Three-chamber social approach test
 3 months
Social memory1
 No change
 Partition test
 3 months
 Not Reported: Circadian sleep/wake cycle, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Seizure


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
UBC ubiquitin C 7316 P63279 LC-MS/MS
Danielsen JM , et al. 2010

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