“…For instance, many DUBs of the USP family encode substrate interaction motifs and cleave ubiquitin chains from substrates (base cleavage) [22], while other DUBs prefer to cleave ubiquitin chains from the middle (endo-cleavage, e.g., most OTU DUBs [61]) or from the distal or proximal end of the chain (distal exo cleavage, e.g., MINDY [51,62], and proximal exo-cleavage, e.g., USP5 [63], respectively). In addition, some DUBs display exquisite linkage specificity (e.g., some members of the OTUs [61], JAMMs [64][65][66], [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 diffi...…”