A schematic of the base of primary cilium showing the MC (basal body) and the proposed function of CC2D2A at SDA. The MC includes triplet MTs (purple cylinders) that continue as the doublet MTs of the axoneme (pink cylinders). The plus and minus ends of MTs are marked. The proteins localized to the cilium and MC are indicated. Nine extensions of each MT bundle at the border of MC and transition zone represent the SDA (blue–green–yellow pyramids) and distal appendages (blue rods). The proteins localized to SDA are shown in an order from centre to periphery, based on the current experimental evidence. The SDA anchors MT arrays and helps in the docking of transport vesicles at the base of cilium. The distal appendages help in tethering the MC to the plasma membrane, separating the cilium compartment from the cytoplasm. The green circle at the far end of the distal appendage, on the right side, represents a Rab8a-tagged vesicle. Rab8a may help tether plasma membrane to distal appendages with support from Odf2 and CC2D2A. Inset shows the top view of MC at the level of SDA, which are shown anchored to MT. The electron micrographs on the right show a cross-sectional view at the level indicated: doublet axoneme (top), at the level of appendages (middle) and triplet MC (basal body) (bottom).

A schematic of the base of primary cilium showing the MC (basal body) and the proposed function of CC2D2A at SDA. The MC includes triplet MTs (purple cylinders) that continue as the doublet MTs of the axoneme (pink cylinders). The plus and minus ends of MTs are marked. The proteins localized to the cilium and MC are indicated. Nine extensions of each MT bundle at the border of MC and transition zone represent the SDA (blue–green–yellow pyramids) and distal appendages (blue rods). The proteins localized to SDA are shown in an order from centre to periphery, based on the current experimental evidence. The SDA anchors MT arrays and helps in the docking of transport vesicles at the base of cilium. The distal appendages help in tethering the MC to the plasma membrane, separating the cilium compartment from the cytoplasm. The green circle at the far end of the distal appendage, on the right side, represents a Rab8a-tagged vesicle. Rab8a may help tether plasma membrane to distal appendages with support from Odf2 and CC2D2A. Inset shows the top view of MC at the level of SDA, which are shown anchored to MT. The electron micrographs on the right show a cross-sectional view at the level indicated: doublet axoneme (top), at the level of appendages (middle) and triplet MC (basal body) (bottom).

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The primary cilium originates from the mother centriole and participates in critical functions during organogenesis. Defects in cilia biogenesis or function lead to pleiotropic phenotypes. Mutations in centrosome-cilia gene CC2D2A result in Meckel and Joubert syndromes. Here we generate a Cc2d2a(-/-) mouse that recapitulates features of Meckel synd...

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... role is less clear. Additional investigations are required to determine whether distinct proteins are assembled directly at the MC, or if a preassembled complex is attached to the MC to generate SDA. The catalytically inactive transglutaminase-like domain in CC2D2A is a good candidate for providing the MT interaction surface for SDA assembly (see Fig. 8 for a ...
Context 2
... MKS-JBTS-associated proteins such as CEP290, Tectonic1 and B9D1 (ref. 21). It appears that the SDA region is at the base of the ciliary transition zone where triplet MTs of the MC terminate and doublet MTs of the axoneme begin 4,53,54 . The overlap in RPGR and CC2D2A immunostaining, reported here (see Fig. 7b), is consistent with this model (see Fig. 8) and with their interaction with CEP290 (refs 16,55); however, these proteins might exist in distinct protein complexes in SDA or transition zone 12,14,56 . A substantial fraction of mutant MEFs revealed the docking of the MC with the ciliary vesicle but no transition zone was apparent, suggesting a requirement of CC2D2A in transition ...

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... The most common features of ciliopathy include cystic liver and/or kidney, blindness, neural tube defects, brain anomalies, mental disability, skeletal abnormalities, obesity, and infertility, among others (Oud et al., 2017). Genomic and bioinformatics research has revealed that some primary cilia genes are linked to psychiatric disorders, such as the genes CC2D2A and Disc1, which are involved in ciliogenesis (Shen et al., 2008;Marley and von Zastrow, 2010;Veleri et al., 2014), and their defects can lead to psychiatric disorders, including Joubert syndrome (Bachmann-Gagescu et al., 2012), mental retardation (Noor et al., 2008;Shi et al., 2012), Meckel syndrome (Tallila et al., 2008), and Bardet Biedl syndrome (BBS) (Haq et al., 2019). In addition, several signaling pathways and crucial factors highly associated with schizophrenia, such as Wnt signaling, the fibroblast growth factor signaling system, neuronal migration, and the dopamine hypothesis, are dependent on the complete functionality of the cilium, although the specific mechanism is not yet well understood (Marley and von Zastrow, 2010;Muraki and Tanigaki, 2015;Narla et al., 2017;Hoseth et al., 2018). ...
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... [8][9][10] Although a number of related coding genes have been reported and included in RetNet (https://sph.uth.edu/retnet), [11][12][13][14][15][16][17][18][19][20] the noncoding genes that influence the macula and cones have rarely been considered. miR-183C (composed of miR-182, miR-183, and miR-96) is abundantly expressed in human and animal retinas. ...
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... However, it remains unknown whether this recruitment is mediated by direct interactions or through indirect mediators. The base of the conical SDA is formed by CC2D2A, ODF2 and CEP128, which form the inner SDA layer (Ishikawa et al., 2005;Kashihara et al., 2019;Tateishi et al., 2013;Veleri et al., 2014). Subsequently, CCDC120, CEP110 (also known as CNTRL), CCDC68 and NDEL1 interact with ODF2 and CEP128, establishing an intermediate layer (Chong et al., 2020;Huang et al., 2017;Kashihara et al., 2019;Tateishi et al., 2013). ...
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... Another subdistal appendage [75] and ciliary transition zone protein [76] that associates with recycling endosome associated MICAL-L3 and the small GTPase, Rab8, is CC2D2A. Mutations in CC2D2A (coiled-coil and C2-domains containing protein 2A) are the second most common genetic cause for the ciliopathy, Joubert syndrome [77,78], and can also result in the genetically related Meckel syndrome, which is a perinatal-lethal disorder characterized by encephalocele, polydactyly, cystic kidneys and liver fibrosis [79]. ...
... In murine models, CC2D2A −/− mice resulted in embryonic lethality with multi-organ defects related to cilia biogenesis (figure 4). Importantly, CC2D2A loss prevents subdistal appendage assembly [75]. Here we propose a model, that like cenexin, CC2D2A may provide additional levels of regulation for cargo sorting at mother centriole appendages. ...
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... Coiled-coil and C2 domain containing 2A, encoded by CC2D2A, is expressed in multiple human adult tissues, particularly in brain, prostate, pancreas, kidney, lung, liver and retina (Noor et al., 2008). CC2D2A localizes and functions at the transition zone (TZ) (Gorden et al., 2008) where it has a role in cilia assembly and interacts with MKS-JBTS associated proteins (Tables S1 and S2) Garcia-Gonzalo et al., 2011;Lewis et al., 2019;Ojeda Naharros et al., 2017;Tallila et al., 2008;Veleri et al., 2014). Mutations in CC2D2A cause a spectrum of clinical phenotypes, ranging from isolated rod-cone dystrophy (RCD) (Mejecase et al., 2019) to JBTS (Bachmann-Gagescu et al., 2012;Gorden et al., 2008;Noor et al., 2008) and MKS (Mougou-Zerelli et al., 2009;Szymanska et al., 2012;Tallila et al., 2008Tallila et al., , 2009. ...
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Background Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via tissue‐specific preservation of the amount of expressed functional protein. Methods We systematically reviewed and annotated genetic variants and clinical presentations reported in CEP120‐ and CC2D2A‐associated disease and we combined in silico and ex vivo approaches to study tissue‐specific transcripts and identify molecular targets for exon skipping. Results We confirmed more severe clinical presentations associated with truncating CC2D2A mutations. We identified and confirmed basal exon skipping in the kidney, with possible relevance for organ‐specific disease manifestations. Finally, we proposed a multimodal approach to classify exons amenable to exon skipping. By mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. Conclusion Genotype‐phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.
... Further to which, the top two over-expressed genes of the COVID-19 specific gene signature are coiled-coil and C2 domain containing 2A (CC2D2A) and Homeostatic Iron Regulator (HFR). CC2D2A plays a critical role in cilia formation (Veleri et al., 2014). Primary cilia microtubule-based sensory organelles that detect mechanical and chemical stimuli and are found in almost all cells in the body (Garcia-Gonzalo and Reiter, 2012). ...
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