The OTUD7A gene encodes a member of a family of deubiquitinating enzymes (DUBs; see 603478), which are proteases that specifically cleave ubiquitin (191339) linkages from proteins targeted for degradation. OTUD7A also localizes to the postsynaptic density in the brain, suggesting a role in synapse development and maturation (summary by Uddin et al., 2018).

OTUD7A belongs to a DUB subfamily characterized by an ovarian tumor (OTU) domain (Kayagaki et al., 2007).

Kayagaki et al. (2007) identified ovarian tumor domain (OTU)-containing protein 7A (OTUD7A) in a small interfering RNA (siRNA)-based screen for OTU deubiquitinating enzyme (DUB) family members. The 3,042-basepair mRNA contains an open reading frame (ORF) predicting a 926-amino acid protein. In addition to an OTU domain, the protein contains an A20-like zinc finger (ZNF A20) domain at the carboxy terminus.

Uddin et al. (2018) found highest expression of the OTUD7A gene in human brain tissue compared to other human tissues. Network analysis suggested that the OTUD7A gene plays an important role in a brain-specific protein module and is likely involved in brain-specific synaptic signaling. Otud7a was also identified in the developing mouse brain during early postnatal stages when dendrites and dendritic spines are forming. Gene expression was localized to neuronal soma and dendrites in a punctate pattern, and also showed localization to the postsynaptic region of excitatory synapses.

In the mouse brain, Yin et al. (2018) found high expression of Otud7a in primary cortical neurons with enrichment at dendritic spines and membrane compartments in the cell body.

The OTUD7A gene maps to chromosome 15q13.3 (Kayagaki et al., 2007).

Garret et al. (2020) demonstrated that OTUD7A plays a role in proteasome function by regulating the steady-state expression level of the P28 proteosome regulator and its alpha (PSME1; 600654) and beta (PSME2; 602161) subunits.

Uddin et al. (2018) performed whole-genome or whole-exome sequencing in over 6,000 individuals with a neurodevelopmental disorder who did not have a 15q13.3 microdeletion (see the 15q13.3 deletion syndrome, 612001) and detected 8 de novo mutations in genes within the breakpoint interval (BP4-BP5), 3 of which occurred in the OTUD7A gene. In 2 sibs (proband is case 3) with autism spectrum disorder (ASD), Uddin et al. (2018) identified a de novo heterozygous 9-bp in-frame deletion in the OTUD7A gene (asn492_lys494del). In vitro studies showed that the mutation resulted in normal levels of mutant protein production, but that mutant protein was not able to rescue the abnormal dendritic phenotype of mouse neurons with heterozygous deletion of chromosome 15q13 (Df(h15q13)+/- mouse mutants; see ANIMAL MODEL). Expression of mutant OTUD7A in cultured wildtype neurons significantly reduced dendritic spine length, consistent with a mild dominant-negative effect. Studies of patient cells were not performed. Uddin et al. (2018) also identified 2 additional unrelated patients with ASD associated with de novo heterozygous intronic variants in the OTUD7A gene (c.-223+11014A-G and c.1150+935del); functional studies of these variants and studies of patient cells were not performed.

Kozlova et al. (2022) performed targeted sequencing of genes within schizophrenia-associated copy-number variants (CNVs) in 1,779 schizophrenia cases and 1,418 controls. They identified 3 patients with rare variants in the OTUD7A gene, which is located within the chromosome 15q13.3 deletion interval that is associated with a variety of neuropsychiatric phenotypes. None of the variants reached statistical significance. The rare variants included arg89 to ter (R89X, rs757148409), glu136 to ter (E136X), and asn492_lys494del (c.1474_1482del). The asn492_lys494del variant had been identified by Uddin et al. (2018) in 2 sibs with autism. Kozlova et al. (2022) modeled the OTUD7A variant R89X in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR-Cas9 engineering. The mutant iNs showed an approximately 50% decrease in OTUD7A protein expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 (138248) and PSD95 (602887), and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, transcriptomic analysis showed that the set of genes downregulated by OTUD7A loss of function was enriched for those relating to synapse development and function and was associated with schizophrenia and other neuropsychiatric disorders. Hamosh (2022) found that, in gnomAD, the asn492_lys494del variant had the highest minor allele frequency in South Asians (0.0001001, 3/29,964 alleles), but was also seen in 1 African American and 3 non-Finnish Europeans. Hamosh (2022) found the R89X variant (rs757148409) in 1 Finnish and 1 non-Finnish European in gnomAD, for an allele frequency of 0.0000080.

Neurodevelopmental Disorder With Hypotonia And Seizures

In a 28-month-old boy, born of distantly consanguineous Portuguese parents, with neurodevelopmental disorder with hypotonia and seizures (NEDHS; 620790), Garret et al. (2020) identified a homozygous missense mutation in the OTUD7A gene (L233F; 612024.0001). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent, both of whom had learning disabilities. The variant was not present in the gnomAD database. Patient fibroblasts showed decreased enzymatic activity of the 20S proteasome complex compared to controls. Although levels of the 20S and 26S proteosomes were normal, there were decreased amounts of the PA28 (see PA28A, 600654)-20S and free PA28 complexes, as well as decreased levels of certain PA28 and 20S proteasome subunits. Similar findings were observed in OTUD7A-null HAP1 cells. The reduced proteasome activity was associated with accumulation of insoluble proteins modified with K48-linked ubiquitin chains targeted for proteasome-mediated degradation, indicating disrupted protein homeostasis.

In a 3-year-old boy with NEDHS, Suzuki et al. (2021) identified compound heterozygous loss of the OTUD7A gene. He had a de novo heterozygous frameshift mutation (612024.0002) and a de novo heterozygous 1.6-Mb microdeletion of chromosome 15q13.3, which included the OTUD7A gene (see 612001). The point mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing, whereas the deletion was identified through copy number variant analysis. Neither parent carried the mutation or the deletion. Studies of patient cells were not performed, but homozygous expression of the frameshift mutation in the C. elegans homolog resulted in impaired locomotion and disturbed synaptic transmission (see ANIMAL MODEL). The authors concluded that the frameshift mutation is a loss-of-function allele and that the motor defects could have resulted from reduced synaptic transmission from motor neurons.

Fejgin et al. (2014) found that mutant mice with a heterozygous 15q13.3 microdeletion (Df(h15q13)/+) showed marked changes in neuronal excitability in acute seizure assays, with increased propensity to develop myoclonic and absence-like seizures, but decreased propensity for clonic and tonic seizures. Mutant mice had impaired long-term spatial reference memory and a decreased theta frequency in the hippocampus and prefrontal cortex, as well as auditory processing deficits similar to those observed in schizophrenia. The neurologic abnormalities in these mice recapitulated some of the phenotypic features observed in humans with 15q13.3 deletions.

Using RNA sequencing, Uddin et al. (2018) found that Df(h15q13)/+ mice had significantly decreased expression of several genes involved in forebrain cortical development, including Chrna7 (118511) and Otud7a. This decreased expression was associated with a small, but significant, reduction in dendritic spine density, mature mushroom-shaped spines, dendritic length, and dendritic arborization in the frontal cortex compared to wildtype. Isolated cortical neurons from heterozygous mutant mice showed similar abnormalities. Expression of wildtype OTUD7A was able to rescue the abnormalities in dendritic spine density, length, and the proportion of mushroom and stubby spines, but expression of CHRNA7, KLF13 (605328), or FAN1 (613534), other genes within the candidate region, was unable to rescue these defects. However, CHRNA7 was able to rescue dendrite outgrowth, suggesting some potential overlap in function. Uddin et al. (2018) concluded that OTUD7A is a critical gene in the 15q13.3 microdeletion syndrome.

Yin et al. (2018) found that homozygous Otud7a-null mice had preweaning growth delay and delayed motor milestones, increased seizure-like activity, and impaired vocalization, although memory and learning appeared to be normal as measured by fear conditioning and novel object recognition tests. Homozygous and heterozygous-null mice showed impaired acoustic startle response compared to wildtype, and female mutant mice had reduced prepulse inhibition, all of which may represent features of schizophrenia. Primary cortical neurons derived from Otud7a-null mice showed a significant reduction in dendritic spine density compared to controls, and this defect could be rescued by expression of wildtype Otud7a, although there were no apparent defects in dendritic growth or dendritic complexity. Primary neurons from mutant mice also showed a decrease in functioning excitatory synapses. Yin et al. (2018) concluded that OTUD7A deficiency largely accounts for the human phenotypes associated with 15q13.3 deletion syndrome and that OTUD7A is important in the regulation of dendritic spine density and activity.

The OTUD7A homolog in C. elegans is otub2, which is expressed in the nervous system. Suzuki et al. (2021) found that C. elegans carrying a homozygous CRISPR/Cas9-generated mutation in the otub2 gene that corresponded to a frameshift mutation identified in a human patient (612024.0002) developed normally, but had impaired locomotion with disturbed movement patterns and smaller movement amplitudes compared to wildtype. This abnormality was not observed in heterozygous mutant worms. The authors concluded that the frameshift mutation is a loss-of-function allele and that the motor defects could have resulted from reduced synaptic transmission from motor neurons to body wall muscles.