Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features

Abstract

Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.

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

“…Given the potential implication of the OTU deubiquitinase family in the regulation of proteasome populations and activities, we explored the impact of OTUD7A defects on the intracellular pools of 20S and 26S proteasome complexes either in fibroblasts derived form a healthy subject (CTRL1) or our patient carrying the homozygous missense c.697C>T variant. As pathogenic 15q13.3 microdeletions are associated with incomplete penetrance and highly variable expressivity at the heterozygous state, the use of material derived from heterozygous c.697C>T carriers were not necessary for our experiments, because such material would not be necessarily informative.…”

“…Ubiquitination is a reversible posttranslational modification, mediated by deubiquitinating enzymes, playing also a critical role in synapse formation and function . Pathogenic variants in deubiquitinases such as USP9X, USP27X and OTUD6B have been already associated with recessive human diseases responsible for mental retardation (MIM 300919, 300 984 and 617 452, respectively) …”

“…Given the potential implication of the OTU deubiquitinase family in the regulation of proteasome populations and activities, 19 we explored the impact of OTUD7A defects on the intracellular pools of Figure 1A).…”

“…26 Pathogenic variants in deubiquitinases such as USP9X, USP27X and OTUD6B have been already associated with recessive human diseases responsible for mental retardation (MIM 300919, 300 984 and 617 452, respectively). 19,27,28 In 2018, a first report detailing two siblings with ASD and a de novo 9 bp in frame OTUD7A deletion (p.Asn492_Lys494del) and…”

“…19 Indeed, it was previously shown that cells from subjects suffering from cognitive impairment and carrying biallelic deletions in the OTUD6B gene fail to incorporate 19S subunits into 26S proteasomes. 19 Here, we identify OTUD7A as a new member of the growing family of deubiquitinases whose functional disruption has an impact on the intracellular proteasome pools. Interestingly and unlike OTUD6B, OTUD7A seems to be required for PA28 expression, even though the underlying mechanism remains ill-defined.…”