Alternative titles; symbols
HGNC Approved Gene Symbol: OTUD5
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:48,922,024-48,958,381 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Multiple congenital anomalies-neurodevelopmental syndrome, X-linked | 301056 | X-linked recessive | 3 |
The OTUD5 gene encodes a K48/K63 linkage-specific deubiquitinase that belongs to a family of deubiquitinating enzymes (DUBs; see 603478). These enzymes are proteases that specifically cleave ubiquitin (191339) linkages, negating the action of ubiquitin ligases. OTUD5-mediated K48-linked cleavage protects substrates from proteasomal degradation, and OTUD5-mediated K63-linked cleavage alters intracellular signaling (summary by Beck et al., 2021).
DUBA belongs to a DUB subfamily characterized by an ovarian tumor (OTU) domain (Kayagaki et al., 2007).
Kayagaki et al. (2007) identified deubiquitinating enzyme A (DUBA) in a small interfering RNA (siRNA)-based screen as a regulator of type I interferon (e.g., 147660) production. In addition to an OTU domain, DUBA contains a ubiquitin action motif (UIM) at its carboxy terminus. The 2,759-basepair mRNA contains an open reading frame (ORF) predicting a 571-amino acid protein.
Kayagaki et al. (2007) demonstrated that reduction of DUBA augmented the pattern recognition receptor (PRR)-induced type I interferon response in transfected HEK293 cells, whereas ectopic expression of DUBA had the converse effect. DUBA bound tumor necrosis factor receptor-associated factor-3 (TRAF3; 601896), an adaptor protein essential for type I interferon response. TRAF3 is an E3 ubiquitin ligase that preferentially assembled lys63-linked polyubiquitin chains in cotransfection assays. DUBA selectively cleaved the lys63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase-1 (604834). A discrete ubiquitin interaction motif within DUBA was required for efficient deubiquitination of TRAF3 and optimal suppression of type I interferon. Kayagaki et al. (2007) concluded that their data identified DUBA as a negative regulator of innate immune responses.
Rutz et al. (2015) showed that the deubiquitylating enzyme DUBA is a negative regulator of IL17A (603149) production in T cells. Mice with Duba-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. Duba interacted with the ubiquitin ligase Ubr5 (608413), which suppressed Duba abundance in naive T cells. Duba accumulated in activated T cells and stabilized Ubr5, which then ubiquitylated ROR-gamma-t (see RORC, 602943) in response to TGFB (190180) signaling. Rutz et al. (2015) concluded that their data identified DUBA as a cell-intrinsic suppressor of IL17 production.
Beck et al. (2021) determined that the normal K48 linkage-specific deubiquitylation activity of OTUD5 prevents the degradation of multiple chromatin remodelers that coordinate gene expression during neuroectodermal differentiation.
The OTUD5 gene maps to chromosome Xp11.23 (Kayagaki et al., 2007).
In 3 affected males from a large multigenerational family with X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND; 301056), Tripolszki et al. (2021) identified a hemizygous missense mutation in the OTUD5 gene (E200K; 300713.0001). The mutation, which was found by genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database (v2.1.1). The variant segregated with the disorder in the family; there were 4 confirmed unaffected female carriers. Functional studies of the variant and studies of patient cells were not performed.
In 10 patients from 7 unrelated families with MCAND, Beck et al. (2021) identified 7 different hemizygous mutations in the OTUD5 gene (see, e.g., 300713.0002-300713.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families except the patient in family 2 who had a de novo mutation. There were 5 missense mutations, 1 splice site, and 1 in-frame deletion. None were present in the gnomAD database. In vitro functional studies of some of the mutations showed that they resulted in a loss of function by various effects, including a reduction in protein levels, mislocalization of the protein, or disruption of K48- or K63-linked ubiquitin chain cleavage. Induced pluripotent stem cells derived from 1 patient showed defects in neuroectodermal differentiation compared to controls. Cellular knockdown of OTUD5 resulted in similar differentiation abnormalities that could not be rescued by mutant OTUD5. Expression of some of the variants in mice resulted in lethality. Detailed proteomic experiments using mass spectrometry identified chromatin remodelers as substrates of OTUD5, suggesting that OTUD5 controls neuroectodermal cell fate by regulating chromatin accessibility which enables activation of transcriptional networks that drive differentiation. Beck et al. (2021) concluded that OTUD5 regulates cell fate decisions during embryogenesis by cleaving K48-ubiquitin linkage on substrates. Reduction of this activity through mutation results in defective embryogenesis and leads to a multiple congenital anomaly syndrome. Thus, aberrant degradation of chromatin regulators is a major disease mechanism, similar to the pathogenetic mechanisms of Coffin-Siris syndrome (see, e.g., CSS1, 135900) and Cornelia de Lange syndrome (see, e.g., CDLS1, 122470), both of which show some overlapping clinical features.
In 3 affected males from a large multigenerational family with X-linked multiple congenital anomalies-neurodevelopmental disorder (MCAND; 301056), Tripolszki et al. (2021) identified a hemizygous c.598G-A transition (c.598G-A, NM_017602.3) in exon 2 of the OTUD5 gene, resulting in a glu200-to-lys (E200K) substitution in the highly conserved catalytic domain. The mutation, which was found by genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database (v2.1.1). The variant segregated with the disorder in the family; there were 4 unaffected female carriers. Several other deceased male family members from prior generations were similarly affected, but genetic studies on these patients could not be performed. Functional studies of the variant and studies of patient cells were not performed. The phenotype was severe, and most died in early childhood.
In 2 brothers (P1 and P2, family 1) with X-linked multiple congenital anomalies-neurodevelopmental disorder (MCAND; 301056), Beck et al. (2021) identified a hemizygous c.1480G-A transition in the OTUD5 gene, predicted to result in a gly494-to-ser (G494S) substitution. However, the mutation occurred at a splice site junction and caused abnormal intron retention associated with a reduction in OTUD5 mRNA and protein levels. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient-derived induced pluripotent stem cells showed defects in neuroectoderm differentiation as measured by the expression of neural crest marker proteins. Knock-in of the G494S mutation into mice resulted in embryonic lethality. The findings were consistent with a loss of function. The patients had a severe phenotype resulting in death in infancy.
In a male infant (P4, family 2) with X-linked multiple congenital anomalies-neurodevelopmental disorder (MCAND; 301056), Beck et al. (2021) identified a de novo hemizygous c.1055T-C transition in the OTUD5 gene, resulting in a leu352-to-pro (L352P) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the L352P mutation reduced the ability of OTUD5 to cleave specifically at the K48 ubiquitin chain. However, cleavage at K63 was similar to wildtype. Knock-in of the L352P mutation into mice resulted in embryonic lethality. The findings were consistent with a loss of function. The patient had a severe form of the disorder and died at 1 year of age.
In a 14-year-old boy (P6, family 4) with X-linked multiple congenital anomalies-neurodevelopmental disorder (MCAND; 301056), Beck et al. (2021) identified a hemizygous c.820C-T transition in the OTUD5 gene, resulting in an arg274-to-trp (R274W) substitution in a conserved putative nuclear localization sequence. The mutation, which was found through genetic investigation, was inherited from his unaffected mother. It was not present in the gnomAD database. In vitro functional expression studies showed that the mutation caused partial mislocalization of OTUD5 to the cytoplasm and resulted in impaired OTUD5 deubiquitination cleavage activity. The findings were consistent with a loss of function.
In 2 brothers (P8 and P9, family 6) with X-linked multiple congenital anomalies-neurodevelopmental disorder (MCAND; 301056), Beck et al. (2021) identified a hemizygous c.1210C-T transition in the OTUD5 gene, resulting in an arg404-to-trp (R404W) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not present in the gnomAD database. Functional studies of the variant were not performed. The patients were alive at 2 and 8 years of age.
Beck, D. B., Basar, M. A., Asmar, A. J., Thompson, J. J., Oda, H., Uehara, D. T., Saida, K., Pajusalu, S., Talvik, I., D'Souza, P., Bodurtha, J., Mu, W., and 21 others. Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. Sci. Adv. 7: eabe2116, 2021. [PubMed: 33523931] [Full Text: https://doi.org/10.1126/sciadv.abe2116]
Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O'Rourke, K. M., Eby, M., Pietras, E., Cheng, G., Bazan, J. F., Zhang, Z., Arnott, D., Dixit, V. M. DUBA: a deubiquitinase that regulates type I interferon production. Science 318: 1628-1632, 2007. [PubMed: 17991829] [Full Text: https://doi.org/10.1126/science.1145918]
Rutz, S., Kayagaki, N., Phung, Q. T., Eidenschenk, C., Noubade, R., Wang, X., Lesch, J., Lu, R., Newton, K., Huang, O. W., Cochran, A. G., Vasser, M., and 9 others. Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells. Nature 518: 417-421, 2015. [PubMed: 25470037] [Full Text: https://doi.org/10.1038/nature13979]
Tripolszki, K., Sasaki, E., Hotakainen, R., Kassim, A. H., Pereira, C., Rolfs, A., Bauer, P., Reardon, W., Bertoli-Avella, A. M. An X-linked syndrome with severe neurodevelopmental delay, hydrocephalus, and early lethality caused by a missense variation in the OTUD5 gene. Clin. Genet. 99: 303-308, 2021. [PubMed: 33131077] [Full Text: https://doi.org/10.1111/cge.13873]