HGNC Approved Gene Symbol: CCDC22
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38) : X:49,235,470-49,250,520 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Ritscher-Schinzel syndrome 2 | 300963 | X-linked recessive | 3 |
By searching for genes in a region of chromosome X linked to intellectual disability, Voineagu et al. (2012) identified CCDC22. They found that CCDC22 was expressed in all adult tissues examined and in fetal liver and brain. Expression was highest in prostate and lowest in skeletal muscle.
Starokadomskyy et al. (2013) reported that the deduced 627-amino acid CCDC22 protein has an N-terminal conserved domain and a C-terminal coiled-coil domain that is similar to structural maintenance of chromosomes (SMC) proteins (see SMC1A, 300040). Database analysis revealed variable CCDC22 expression in human tissues, with highest expression in a number of blood cell lineages, moderate expression in lung, heart, prostate, thyroid, and thymus, and lower expression in other tissues. Quantitative RT-PCR of 8 mouse tissues detected highest expression in lung and lowest expression in muscle. Western blot analysis showed highest expression of mouse Ccdc22 in thymus and pancreas, with little to no expression in kidney, muscle, small bowel, and testis. Fluorescence-tagged CCDC22 was expressed in a punctate perinuclear distribution in transfected HeLa cells.
By mass spectrometric analysis of proteins that affinity-purified with COMMD1 (607238), COMMD9 (612299), and COMMD10 (616704), Starokadomskyy et al. (2013) identified CCDC22, in addition to other COMM domain proteins. Reciprocal immunoprecipitation and protein pull-down assays revealed that CCDC22 interacted with all 10 COMM domain proteins examined. Silencing of CCDC22 in U2OS cells relocalized COMMD1 from a strong nuclear staining pattern to large perinuclear foci, and relocalized COMMD10 from small perinuclear foci to large perinuclear foci. Domain analysis revealed that the conserved N-terminal domain of CCDC22 bound the COMM domain of COMMD1. CCDC22 and COMM domain proteins were also detected in protein complexes with cullins (see CUL1, 603134), which function as ligases for ubiquitination of target proteins. Epitope-tagged COMMD8 (616656) bound CCDC22, CUL1, and CUL3 (603136) in HeLa cells and promoted ubiquitination and degradation of the NF-kappa-B (see 164011) inhibitor I-kappa-B-alpha (NFKBIA; 164008). Silencing of COMMD8 (616656) or CCDC22 in HEK293 cells reduced TNF (191160)-dependent activation of several NF-kappa-B pathway genes. Starokadomskyy et al. (2013) concluded that the CCDC22-COMMD8 complex regulates I-kappa-B turnover and NF-kappa-B activation.
Singla et al. (2019) demonstrated that the human COMMD/CCDC22/CCDC93 (620553) (CCC) and retriever complexes shared VPS35L (618981) as a common subunit. The CCC complex, but not retriever, was required to maintain normal endosomal levels of phosphatidylinositol-3-phosphate (PI3P). Depletion of CCC led to elevated PI3P levels, enhanced recruitment and activation of WASH (see 613632), excess endosomal F-actin, and trapping of internalized receptors. Mechanistically, CCC regulated phosphorylation and endosomal recruitment of the PI3P phosphatase MTMR2 (603557). The authors concluded that regulation of PI3P levels by CCC is critical to protein recycling in the endosomal compartment.
Fedoseienko et al. (2018) showed that liver-specific knockout of COMMD1 (607238), COMMD6, or COMMD9 (612299) in mice resulted in massive reduction of the protein levels of all 10 COMMDs. This decrease coincided with the destabilization of the CCC complex core (CCDC22, CCDC93, and VPS35L) and resulted in decreased cell surface LDLR (606945) and LRP1 (107770) and increased plasma LDL cholesterol. Fedoseienko et al. (2018) then knocked out CCDC22 in mouse liver and found that CCDC22 deficiency also destabilized the complete CCC complex and resulted in elevated plasma LDL cholesterol levels. Fedoseienko et al. (2018) concluded that their studies found an essential role for the COMMD proteins in maintaining the CCC complex during endosomal LDLR and LRP1 trafficking.
Hartz (2011) mapped the CCDC22 gene to chromosome Xp11.23 based on an alignment of the CCDC22 sequence (GenBank AJ005890) with the genomic sequence (GRCh37).
In affected members of a family (IGOLD #586) with syndromic X-linked intellectual disability consistent with Ritscher-Schinzel syndrome-2 (RTSC2; 300963), Voineagu et al. (2012) identified a hemizygous splice site mutation in the CCDC22 gene (300859.0001). Patient cells showed a 5-fold decrease in mRNA levels as well as increased levels of abnormally spliced transcripts retaining intron 1. The proband was 1 of 208 patients who underwent X-chromosome resequencing and had previously been part of a large cohort studied by Tarpey et al. (2009).
In 2 brothers, born of unrelated Austrian parents, with Ritscher-Schinzel syndrome-2, Kolanczyk et al. (2015) identified a hemizygous missense mutation in the CCDC22 gene (Y557C; 300859.0002). The mutation was found by whole-exome sequencing and segregated with the disorder in the family.
In affected male members of a family (IGOLD #586) with syndromic X-linked intellectual disability consistent with Ritscher-Schinzel syndrome-2 (RTSC2; 300963), Voineagu et al. (2012) identified a hemizygous c.49A-G transition in exon 1 of the CCDC22 gene close to the 5-prime splice site of intron 1. Although the transition was predicted to result in a thr17-to-ala (T17A) substitution, patient cells showed a 5-fold decrease in mRNA levels as well as increased levels of abnormally spliced transcripts retaining intron 1. There was no evidence for nonsense-mediated mRNA decay, and Voineagu et al. (2012) concluded that the mutation interfered with efficient transcription of CCDC22. The mutation, which was found by examining gene expression profiles of lymphoblast cell lines followed by candidate gene sequencing in patients with X-linked intellectual disability, segregated with the disorder in the family. The patient was 1 of 208 patients who underwent X-chromosome resequencing and had previously been part of a large cohort studied by Tarpey et al. (2009).
In 2 brothers, born of unrelated Austrian parents, with Ritscher-Schinzel syndrome-2 (RTSC2; 300963), Kolanczyk et al. (2015) identified a hemizygous c.1670A-G transition (c.1670A-G, NM_014008.4) in exon 15 of the CCDC22 gene, resulting in a tyr557-to-cys (Y557C) substitution at a conserved residue in the C-terminally located coiled-coil domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the Exome Variant Server database. The variant was filtered against the dbSNP (build 132) and 1000 Genomes Project databases. Lymphocytes from 1 of the patients showed a 50% decrease in CCDC22 protein levels compared to controls, and there was increased abundance of the WASH1 (613632) protein. Kolanczyk et al. (2015) noted that RTSC1 (220210) is caused by mutation in the gene encoding strumpellin (KIAA0196; 610657), which is part of the WASH complex.
Fedoseienko, A., Wijers, M., Wolters, J. C., Dekker, D., Smit, M., Huijkman, N., Kloosterhuis, N., Klug, H., Schepers, A., Willems van Dijk, K., Levels, J. H. M., Billadeau, D. D., Hofker, M. H., van Deursen, J., Westerterp, M., Burstein, E., Kuivenhoven, J. A., van de Sluis, B. The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking. Circ. Res. 122: 1648-1660, 2018. [PubMed: 29545368] [Full Text: https://doi.org/10.1161/CIRCRESAHA.117.312004]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/21/2011.
Kolanczyk, M., Krawitz, P., Hecht, J., Hupalowska, A., Miaczynska, M., Marschner, K., Schlack, C., Emmerich, D., Kobus, K., Kornak, U., Robinson, P. N., Plecko, B., Grangl, G., Uhrig, S., Mundlos, S., Horn, D. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome. Europ. J. Hum. Genet. 23: 633-638, 2015. Note: Erratum: Europ. J. Hum. Genet. 23: 720 only, 2015. [PubMed: 24916641] [Full Text: https://doi.org/10.1038/ejhg.2014.109]
Singla, A., Fedoseienko, A., Giridharan, S. S. P., Overlee, B. L., Lopez, A., Jia, D., Song, J., Huff-Hardy, K., Weisman, L., Burstein, E., Billadeau, D. D. Endosomal PI(3)P regulation by the COMMD/CCDC22/CCC93 (CCC) complex controls membrane protein recycling. Nature Commun. 10: 4271, 2019. Note: Electronic Article. [PubMed: 31537807] [Full Text: https://doi.org/10.1038/s41467-019-12221-6]
Starokadomskyy, P., Gluck, N., Li, H., Chen, B., Wallis, M., Maine, G. N., Mao, X., Zaidi, I. W., Hein, M. Y., McDonald, F. J., Lenzner, S., Zecha, A., Ropers, H.-H., Kuss, A. W., McGaughran, J., Gecz, J., Burstein, E. CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappa-B signaling. J. Clin. Invest. 123: 2244-2256, 2013. [PubMed: 23563313] [Full Text: https://doi.org/10.1172/JCI66466]
Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genet. 41: 535-543, 2009. [PubMed: 19377476] [Full Text: https://doi.org/10.1038/ng.367]
Voineagu, I., Huang, L., Winden, K., Lazaro, M., Haan, E., Nelson, J., McGaughran, J., Nguyen, L. S., Friend, K., Hackett, A., Field, M., Gecz, J., Geschwind, D. CCDC22: a novel candidate gene for syndromic X-linked intellectual disability. (Letter) Molec. Psychiat. 17: 4-7, 2012. [PubMed: 21826058] [Full Text: https://doi.org/10.1038/mp.2011.95]