OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome

Abstract

Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development.

Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction

“…Here, we report the first case of a homozygous missense variant (NM_130901.2:c.697C>T, p.(Leu233Phe)) in OTUD7A and related proteasome dysfunction found in a patient with severe global developmental delay, language impairment and epileptic encephalopathy. Based on our finding and recent literature, this gene variant may have a significant role in chromosome 15q13.3 microdeletion syndrome, associated with a wide range of neurodevelopmental disorders.…”

“…In support of the findings described in mice, Uddin et al also reported a 5‐year‐old female, with global DD and a genetic deletion that spanned BP4‐BP5 encompassing OTUD7A , but not CHRNA7 , as well as an ASD male individual carrying an inframe deletion in OTUD7A (NM_130901.2( OTUD7A ):c.1474_1482del, p.(Asn492_Lys494del)). The inframe deletion was not inherited from the healthy parents and was also present in the affected brother.…”

“…15q13.3 microdeletion syndrome, caused by heterozygous loss of the critical region encompassing CHRNA7 and OTUD7A , is associated with incomplete penetrance and highly variable expressivity . Rare homozygous or compound heterozygous patients have been also reported, but they present more severe phenotypes including epileptic encephalopathy, hypotonia and poor growth . Although pathogenic microdeletions have been reported independently by several laboratories, the contribution of these two genes in respect to the physio‐pathological mechanisms underlying the neurodevelopmental phenotype associated with this syndrome has remained elusive.…”

“…OTUD7A/CEZANNE2 encodes for an ovarian tumor (OTU) deubiquitinase, which specifically cleaves Lys11‐linked ubiquitin chains . Uddin et al showed that OTUD7A localizes to the dendritic spines of cortical neurons, and its reduced levels in 15q13 microdeletion contributes to the dendritic spine and dendrite outgrowth deficits observed in mouse models with a syntenic heterozygous deletion (Df[h15q13]/+), supporting the idea that OTUD7A is a major regulatory gene for 15q13.3 microdeletion syndrome. Interestingly, biallelic variants of OTUD6B , another member of the OTU family, were recently reported as being responsible for a syndrome associating ID, seizures and dysmorphic features via a 26S proteasome assembly defect, indicating that multiple members of this family may be involved in neurodevelopment.…”

“…Homozygous or compound heterozygous (ie, the condition implicating the presence of two different mutated alleles at a particular gene locus) 15q13.3 microdeletions have occasionally been reported . These individuals present more severe neurodevelopmental problems, with epileptic encephalopathy, hypotonia and poor growth . Although the classical microdeletion had been widely reported in a heterozygous state, the genes responsible for the clinical features associated with 15q13.3 microdeletion syndrome have not clearly been identified.…”