## 3 Genetic NCPs
### The Chaperonins
BBS6 is also called MKKS, because the disease associated with mutations in this gene is also called McKusick-Kaufmann syndrome. The CCT subunits form functional hexadecamers with two octameric rings joined by their openings, which results in a barrel-like structure with a central cavity inside which polypeptide folding occurs [15]. This complex is also named TRiC, for TCP-1 ring complex, where TCP-1 stands for Tailless Complex Polypeptide 1. The integrity and functionality of this complicated multimolecular machine greatly depends on the integrity and functionality of all its individual components, the CCT subunits. For instance, a mutation in one of them may disrupt ring formation and hexadecamer assemblage or make the assemblage unstable and prone to dissociation, especially under the action of stressors. A mutation occurring in subunit 5 of CCT was found to be associated with mutilating, distal sensory neuropathy [56; 57] (Table 1). The functional CCT complex is composed of two hetero-octameric rings associated in a hexadecamer. The reported mutation, p.(His147 Arg), occurred in subunit 5 (CCT5), and the disease was characterized by severe atrophy of the posterior tract of the spinal cord [56; 57]. In vitro studies with human and archaeal purified molecules showed that the mutation, which occurs in the equatorial domain of the chaperonin subunit, impairs some of its properties and functions, resulting in poor oligomeric assembly [107; 108; 109]. More recently, a new disease was described associated with a different missense mutation, p.(Leu224 Val), in CCT5 [58]. While the previously described mutation His147 Arg caused a distal sensory neuropathy more pronounced in adulthood, the newly found mutation is associated with a motor neuropathy of early onset. Noteworthy is the different location of the mutations: His147 Arg is in the equatorial domain, whereas Leu224 Val is in the intermediate domain and appears to have an impact on the conformation of the apical domain, which is involved in substrate recognition and binding, namely functions quite distinct from those of the equatorial domain. The disorders caused by mutations in the BBS genes affect ciliogenesis. Cilia are built with the participation of the BBSsome, an octameric complex composed of seven BBS proteins--BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9--and the protein BBIP10 [110]. BBS6, BBS10, and BBS12 serve as chaperones for BBSome assembly. Defects in the process of ciliogenesis and, consequently, in cilia structure and/or function, lead to a group of disorders called ciliopathies [24; 111]. The Bardet-Biedl syndrome is a genetic disorder with autosomal recessive inheritance, highly prevalent in inbred/consinguingueous populations, and with numerous primary and secondary clinical manifestations, including obesity, retinal degeneration, olfactory deficits, nephropathy, polydactly, development delay, and cognitive or other neurological impairments [24; 112]. About 70-80% of all cases of [PERSON] syndrome result from mutations in _BBS1_ to _BBS18_ genes, with frequent mutations in _BBS1_ and _BBS10_ genes, especially in populations of European and Caucasian descent [113]. The BBS proteins excluded from the BBSome, i.e., BBS6, BBS10, and BBS12, have been classified as chaperonins, since they have high sequence similarity with members of the CCT family [63; 65; 106; 114] (Figure 1). Even if these proteins are not components of the BBSome, mutations in their encoding genes also lead to the same phenotype resulting from the loss or abnormalities of BBSome subunits [24; 65; 115]. Moreover, BBS patients bearing pathogenic variants in the _BBS6_, _BBS10_, and _BBS12_ genes develop a more severe phenotype, with earlier disease onset and greater prevalence of all BBS primary diagnostic features typical of ciliopathies than patients with variants only in the non-chaperonin BBS genes [24; 116].