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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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
