Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation

Abstract

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage–specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency–induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

OTUD5 Variants Associated With X-Linked Intellectual Disability and Congenital Malformation

“…The novel variant that was identified in the current study (c.878A>T, p.Asn293Ile) is located in the OTU domain, which confers deubiquitinase activity. Within the OTU domain, two other pathogenic variants (c.766G>A, p.Asp256Asn and c.820C>T, p.Arg274Trp) have previously been reported ( Figure 3A; Beck et al, 2021). The catalytic activity of OTUD5 is activated when Ser177 is phosphorylated (Huang et al, 2012).…”

“…Individuals 1 and 2 were male siblings and had a novel OTUD5 variant (c.878A>T, Asn293Ile) and sporadic Individual 3 had a known OTUD5 variant (c.1210C>T, Arg404Trp). Including our patients, almost all of the identified OTUD5 variants in affected individuals have been missense variants (Beck et al, 2021;Tripolszki et al, 2021).…”

“…The OTUD5 gene is ubiquitously expressed in human tissues. OTUD5 is an essential component for chromatin remodeling of gene regulatory elements and plays an important role during embryogenesis (Beck et al, 2021).…”

“…Abnormalities in genes encoding OTU DUBs cause various developmental or autoinflammatory diseases (Basar et al, 2020). Recently, a male-specific multiple congenital anomaly disorder caused by pathogenic variants in OTUD5 was reported by two groups (Beck et al, 2021;Tripolszki et al, 2021). Tripolszki et al described a large family with 13 affected individuals (Tripolszki et al, 2021).…”

“…Tripolszki et al described a large family with 13 affected individuals (Tripolszki et al, 2021). Beck et al independently reported ten pediatric cases from seven different families with an OTUD5 pathogenic variant and named this disease LINKage-specific-deubiquitylationdeficiency-induced embryonic defects (LINKED) syndrome (Beck et al, 2021). Affected individuals were characterized by global developmental delay, congenital cardiac anomalies, genitourinary abnormalities, and dysmorphic faces.…”