Table 1.
DUBs whose mutations underlie developmental diseases.
| Gene | Disease | Phenotypes | Mutations | Proposed molecular disease mechanism/substrates |
|---|---|---|---|---|
| AMSH | MIC-CAP syndrome (MIM:614261) | Microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay, and multiple small capillary malformations on the skin [146] | Loss-of-function; recessive mutations that reduce levels, protein interactions, and, catalytic activity [146, 180–183] | Increased RAS and PI3K signaling through dysregulation of endosomal sorting [146] |
| USP7 | Hao-Fountain syndrome (MIM:616863) | Seizures, behavioral abnormalities, hypogonadism, and hypotonia [141] | Loss-of-function; heterozygous deletions or nonsense mutations [141] | Impaired endosomal protein recycling and actin dynamics through loss of USP7-mediated regulation of MAGE-L2-TRIM27 and WASH [141] |
| USP9X | Mental retardation, X-linked 99 (MIM: 300919) | Global developmental delay, intellectual disability, brain abnormalities, hypotonia, motor and speech delay [195, 199] | Loss-of-function; hemizygous mutations [195, 199] | Decreased TGF-β signaling (SMAD4/SMURF1) [199]; impaired centriole duplication (STIL) and cilia formation (NPHP5) [201, 204]; impaired dendritic spine formation and maintenance (ankyrin-G) [144, 145] |
| USP9X | Mental retardation, X-linked 99, syndromic (MIM: 300968) | Female-restricted, intellectual disability associated with characteristic facial features, short stature, cardiac, and structural brain abnormalities [197, 198] | Loss-of-function; heterozygous missense and nonsense mutations [197, 198] | Decreased TGF-β signaling (SMAD4/SMURF1) [199]; impaired centriole duplication (STIL) and cilia formation (NPHP5) [201, 204]; impaired dendritic spine formation and maintenance (ankyrin-G) [144, 145] |
| OTUD5 | LINKED syndrome | Global developmental delay, intellectual disability, central nervous system, craniofacial, cardiac, skeletal, and genitourinary anomalies [41] | Loss-of-function; hemizygous deletion and missense mutations that affect protein levels, localization, and catalytic activity [41] | Impaired chromatin remodeling at neuroectodermal enhancers due to aberrant degradation of chromatin regulators (e.g., ARID1A/B, HDAC2, HCF1) [41] |
| OTUD6B | Multiple congenital anomaly disorder (MIM:617452) | Global developmental delay, feeding difficulties, structural brain abnormalities, and congenital heart disease [40, 214] | Loss-of-function; recessive nonsense and missense mutations [40, 214] | Unclear; possible functions in protein translation [215] and proteasome assembly [40] |
| OTUD7A | 15q13.3 microdeletion syndrome (MIM:612001) | Intellectual disability, seizures, language impairment, dysmorphic features, neuropsychiatric disorders [216–219] | Loss-of-function; deletion mutations [216–219], one report of biallelic missense mutation [221] | Unclear; possible functions in proteasome assembly [221] and DNA damage responses [235] |
| USP27X | Mental retardation, X-linked 105 (MIM: 300984) | Intellectual disability, language impairment, behavioral problems [236] | Loss-of-function; hemizygous nonsense and missense mutations [236] | Unclear; poorly characterized histone-directed DUB [107] |
| ALG13 | Epileptic encephalopathy (MIM: 300884) | Seizures, delayed psychomotor development, dysmorphic features [237, 238] | Loss-of-function; Hemizygous and heterozygous missense and deletion mutations [237] | Reduction in N-linked glycosylation due to reduction of UDP-GlcNAc transferase activity of ALG13 [237, 238]; unclear whether the OTU domain in ALG13 is active and functional |
Table summarizing DUBs that have been shown to cause congenital disorders when mutated. Disease name, patient phenotypes, type of mutations, and the proposed molecular mechanism of pathogenesis are shown.