Alternative titles; symbols
HGNC Approved Gene Symbol: MCIDAS
Cytogenetic location: 5q11.2 Genomic coordinates (GRCh38) : 5:55,219,564-55,227,315 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q11.2 | Ciliary dyskinesia, primary, 42 | 618695 | Autosomal recessive | 3 |
Multiciliated cells (MCCs) function predominantly in the respiratory system, brain ependyma, and female reproductive tract to produce fluid flow along epithelial surfaces. MCIDAS functions postmitotically in epithelial cells to stimulate production of multiple centrioles from deuterosomes, which then function as basal bodies that seed motile cilia (Stubbs et al., 2012).
By searching a database for sequences similar to geminin (GMNN; 602842), followed by PCR of a HeLa cell cDNA library, Pefani et al. (2011) cloned a novel gene that they named IDAS, after the cousin of the Gemini in ancient Greek mythology. The deduced 385-amino acid protein contains a putative destruction box-like motif (RxxLxxP), followed by a coiled-coil region, a possible bipartite nuclear localization signal, and a conserved C-terminal domain. IDAS shares low overall similarity with geminin, but the 2 proteins share 53% amino acid identity within the central coiled-coil region. IDAS orthologs were detected in mouse, frog, and fly, with highest conservation within the central coiled-coil region and the C-terminal domain. Real-time PCR detected Idas expression in several cancer cell lines. In situ hybridization of mouse embryos at 12.5 days postcoitus revealed restricted expression in brain, including high levels in the cortical hem and the choroid plexus epithelium. Fluorescence-tagged IDAS localized to nuclei of transfected MCF7 breast cancer cells, with exclusion from nucleoli. In synchronized HeLa cells, endogenous IDAS expression was high during interphase and early mitosis, decreased during anaphase, was undetectable during telophase and cytokinesis, and resumed in early G1. Recombinant IDAS expressed in E. coli formed dimers of about 18.5 kD.
Geminin regulates the cell cycle by directly binding and inhibiting the DNA replication licensing factor CDT1 (605525). Using immunoprecipitation analysis, Pefani et al. (2011) showed that endogenous and transfected IDAS and GMNN interacted in MCF7 cells. Binding of IDAS to geminin reduced the affinity of geminin for CDT1 and directed nuclear accumulation of geminin. The coiled-coil domain of IDAS was sufficient to significantly inhibit geminin binding to CDT1. Depletion of IDAS in HeLa cells via RNA interference caused accumulation of cells in S phase. Conversely, IDAS overexpression in HeLa or 293T cells resulted in multipolar spindles and irregular or multinucleated giant cells. Pefani et al. (2011) concluded that IDAS is a geminin-binding partner that functions in cell cycle progression and may regulate proliferation and differentiation during development.
Stubbs et al. (2012) found that Mci functioned during development of MCCs in Xenopus organs and mouse trachea. In presumptive MCCs of embryonic Xenopus skin, Mci expression induced cell cycle exit, deuterosome-mediated centriole assembly, as measured by formation of Sas6 (SASS6; 609321) foci, and formation of motile cilia. Mci expression was lost upon MCC terminal differentiation. Notch (NOTCH1; 190198) inhibited Mci expression and MCC formation. Mci induced expression of genes involved in MCC differentiation, including Foxj1 (602291) and alpha-tubulin (see 602529). Mci mutants lacking the coiled-coil domain or the C-terminal domain failed to induce MCC differentiation. Stubbs et al. (2012) concluded that MCI has a critical role in formation of MCCs and development of fluid flow in epithelial cells.
In cultured human nasal epithelial cells, Boon et al. (2014) found dynamic and coordinated expression of the MCIDAS, CCNO (607752), and CDC20B (620335) genes during ciliogenesis and the formation of multiciliated cells. The authors also noted that these 3 gene lie adjacent to each other in a conserved genomic region on chromosome 5q11.
Using in situ hybridization, Kyrousi et al. (2015) showed that Mcidas and Gemc1 (GMNC; 614448) were expressed during late mouse embryogenesis in radial glial cells (RGCs) that would give rise to ependymal cells. Overexpression and deletion analyses revealed that expression of Mcidas and Gemc1 was necessary for RGC commitment and differentiation toward ependymal cells. Gemc1 and Mcidas operated in hierarchical order and promoted differentiation of RGCs into ependymal cells by activating expression of the downstream transcription factors Foxj1 and Myb (189990). Mcidas expression was regulated by Gemc1, and Notch signaling negatively regulated the ability of Gemc1 and Mcidas to promote RGC commitment to ependymal cell lineage.
Pefani et al. (2011) determined that the IDAS gene contains 7 exons.
By genomic sequence analysis, Pefani et al. (2011) mapped the IDAS gene to chromosome 5q11.2.
In 9 patients from 5 unrelated families with primary ciliary dyskinesia-42 (CILD42; 618695), Boon et al. (2014) identified 3 different homozygous mutations in the MCIDAS gene (614086.0001-614086.0003). The mutation in the first family was found by whole-exome sequencing and confirmed by Sanger sequencing; mutations in the subsequent families were found by Sanger sequencing of all coding exons of the MCIDAS gene in 59 families with a similar disorder. The mutations segregated with the disorder in all families; none were found in the 1000 Genomes Project database. Ectopic expression of 2 corresponding missense mutations into Xenopus showed that they did not induce the formation of ectopic multiciliated cells as did wildtype MCIDAS, but rather led to a reduction in cell number and an abnormal increase in cell size. The findings indicated that the mutant proteins disabled the activity of endogenous mcidas activity in that organism. Transmission electron microscopy of patient respiratory epithelial cells showed reduced numbers of cilia and a severe decrease in basal bodies compared to controls, indicating that MCIDAS dysfunction causes a reduction in centrioles. Respiratory cells from patients with the MCIDAS R381H mutation showed decreased levels of MCIDAS and severely reduced or absent CCNO expression compared to controls, consistent with MCIDAS working upstream of CCNO in the same pathway. Patient cells also showed severely reduced or absent expression of several axonemal motility-related proteins, including FOXJ1 (602291), DNAH5 (603335), and CCDC39 (613798), as well as CCDC78 (614666).
In a boy (patient 17-1170) with CILD42, Maddirevula et al. (2019) identified a homozygous splice site mutation in the MCIDAS gene (614086.0004). The mutation, which was found by exome sequencing of a cohort of over 2,500 patients with various Mendelian phenotypes, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
By parallel analyses of male mice lacking Gemc1, Mcidas, or Ccno, all of which were infertile, Terre et al. (2019) found that loss of any of these genes impaired formation of multiciliated cells in efferent ducts (EDs), leading to hypocellularity and dilation of seminiferous tubules and rete testes, an indication of fluid backpressure. The fluid backpressure made spermatozoa unable to enter epididymis, resulting in sperm accumulation in EDs and infertility.
In a Belgian patient woman (BEL-1785) who died of primary ciliary dyskinesia-42 (CILD42; 618695), previously reported by DeBoeck et al. (1992), Boon et al. (2014) identified a homozygous c.441C-A transversion in exon 5 of the MCIDAS gene, resulting in a cys147-to-ter (C147X) substitution, predicted to result in a protein lacking the CCDC domain, which is essential for protein function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family: each unaffected parent was a heterozygous carrier. Subsequent sequencing of the MCIDAS gene in 59 families with a similar disorder identified the same homozygous C147X mutation in 2 affected monozygotic twin sisters, born of consanguineous Pakistani parents (family UCL-128). The mutation was not found in the 1000 Genomes Project database. In vitro functional expression studies in Xenopus demonstrated that the mutation impaired the formation of motile cilia.
In 4 affected members of a multigenerational highly consanguineous Israeli kindred (family OI-116/OP-34) with primary ciliary dyskinesia-42 (CILD42; 618695), previously reported by Soferman et al. (1996), Boon et al. (2014) identified a homozygous c.1142G-A transition in exon 7 of the MCIDAS gene, resulting in an arg381-to-his (R381H) substitution at a highly conserved residue. The mutation, which was found by direct Sanger sequencing, segregated with the disorder in the family, and was not present in the 1000 Genomes Project database. In vitro functional expression studies in Xenopus demonstrated that the mutation impaired the formation of motile cilia.
In 2 brothers, born of consanguineous Turkish parents (family BEL-1790) with primary ciliary dyskinesia-42 (CILD42; 618695), Boon et al. (2014) identified a homozygous c.1097G-A transition in exon 7 of the MCIDAS gene, resulting in a gly366-to-asp (G366D) substitution at a highly conserved residue. The mutation, which was found by direct Sanger sequencing, segregated with the disorder in the family, and was not present in the 1000 Genomes Project database. In vitro functional expression studies in Xenopus demonstrated that the mutation impaired the formation of motile cilia.
In a boy (patient 17-1170) with primary ciliary dyskinesia-42 (CILD42; 618695), Maddirevula et al. (2019) identified a homozygous c.717+2T-G transversion (c.717+2T-G, NM_001190787.1) in the MCIDAS gene, predicted to result in a splicing defect. The mutation, which was found by exome sequencing of a cohort of over 2,500 patients with various Mendelian phenotypes, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
Boon, M., Wallmeier, J., Ma, L., Loges, N. T., Jaspers, M., Olbrich, H., Dougherty, G. W., Raidt, J., Werner, C., Amirav, I., Hevroni, A., Abitbul, R., and 15 others. MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nature Commun. 5: 4418, 2014. Note: Electronic Article. [PubMed: 25048963] [Full Text: https://doi.org/10.1038/ncomms5418]
DeBoeck, K., Jorissen, M., Wouters, K., Van der Schueren, B., Eyssen, M., Casteels-VanDaele, M., Corbeel, L. Aplasia of respiratory tract cilia. Pediat. Pulmonol. 13: 259-265, 1992. [PubMed: 1523039] [Full Text: https://doi.org/10.1002/ppul.1950130416]
Kyrousi, C., Arbi, M., Pilz, G.-A., Pefani, D.-E., Lalioti, M.-E., Ninkovic, J., Gotz, M., Lygerou, Z., Taraviras, S. Mcidas and GemC1 are key regulators for the generation of multiciliated ependymal cells in the adult neurogenic niche. Development 142: 3661-3674, 2015. [PubMed: 26395491] [Full Text: https://doi.org/10.1242/dev.126342]
Maddirevula, S., Alzahrani, F., Al-Owain, M., Al Muhaizea, M. A., Kayyali, H. R., AlHashem, A., Rahbeeni, Z., Al-Otaibi, M., Alzaidan, H. I., Balobaid, A., El Khashab, H. Y., Bubshait, D. K., and 36 others. Autozygome and high throughput confirmation of disease genes candidacy. Genet. Med. 21: 736-742, 2019. [PubMed: 30237576] [Full Text: https://doi.org/10.1038/s41436-018-0138-x]
Pefani, D.-E., Dimaki, M., Spella, M., Karantzelis, N., Mitsiki, E., Kyrousi, C., Symeonidou, I.-E., Perrakis, A., Taraviras, S., Lygerou, Z. Idas, a novel phylogenetically conserved geminin-related protein, binds to geminin and is required for cell cycle progression. J. Biol. Chem. 286: 23234-23246, 2011. [PubMed: 21543332] [Full Text: https://doi.org/10.1074/jbc.M110.207688]
Soferman, R., Ne'man, Z., Livne, M., Avital, A., Spirer, Z. Familial nasal acilia syndrome. Arch. Dis. Child. 75: 76-77, 1996. [PubMed: 8813877] [Full Text: https://doi.org/10.1136/adc.75.1.76]
Stubbs, J. L., Vladar, E. K., Axelrod, J. D., Kintner, C. Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation. Nature Cell Biol. 14: 140-147, 2012. [PubMed: 22231168] [Full Text: https://doi.org/10.1038/ncb2406]
Terre, B., Lewis, M., Gil-Gomez, G., Han, Z., Lu, H., Aguilera, M., Prats, N., Roy, S., Zhao, H., Stracker, T. H. Defects in efferent duct multiciliogenesis underlie male infertility in GEMC1-, MCIDAS- or CCNO-deficient mice. Development 146: dev162628, 2019. Note: Electronic Article. [PubMed: 30936178] [Full Text: https://doi.org/10.1242/dev.162628]