Alternative titles; symbols
HGNC Approved Gene Symbol: CEP120
Cytogenetic location: 5q23.2 Genomic coordinates (GRCh38) : 5:123,344,892-123,423,842 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q23.2 | Joubert syndrome 31 | 617761 | Autosomal recessive | 3 |
| Short-rib thoracic dysplasia 13 with or without polydactyly | 616300 | Autosomal recessive | 3 |
Centrioles are conserved microtubule-based organelles that are essential for formation of centrosomes, cilia, and flagella. Centriole duplication involves growth of a procentriole orthogonal to a preexisting centriole. CEP120 is required for centriole elongation from a procentriole (summary by Lin et al., 2013).
Xie et al. (2007) cloned mouse Cep120, and by database analysis, they identified human CEP120. The deduced mouse and human proteins contain 988 and 986 amino acids, respectively, and share 89% identity. Both have an N-terminal C2 calcium/lipid-binding domain and a C-terminal coiled-coil domain. RT-PCR detected Cep120 expression in all mouse tissues examined. Western blot analysis of mouse embryos also showed ubiquitous expression, with highest level in brain, followed by lung and kidney. Expression in adult brain was considerably lower than that in embryonic brain. Immunohistochemical analysis of embryonic mouse brain showed prominent Cep120 expression in pericentrin (PCNT1; 170285)-positive puncta at the ventricular surface, with weaker labeling of pericentrin-positive puncta at other areas of the neocortex.
By Western blot analysis of mouse and human cell lines, Mahjoub et al. (2010) detected CEP120 at an apparent molecular mass of approximately 120 kD. In mouse NIH3T3 fibroblasts and human RPE-1 cells, CEP120 associated with the daughter centriole. During mitosis, CEP120 expression peaked with formation of daughter centrioles. Transmission electron microscopy detected Cep120 along the length of the centriole barrel.
Hartz (2010) mapped the CEP120 gene to chromosome 5q23.2 based on an alignment of the CEP120 sequence (GenBank AK093409) with the genomic sequence (GRCh37).
During neurogenesis, the nuclei of progenitor cells of the proliferative ventricular zone oscillate in a cell cycle-dependent manner called interkinetic nuclear migration (INM). In most cell types, the nucleus closely follows the centrosome during migration; however, in neural progenitors, centrosomes remain near the ventricular zone during INM. Xie et al. (2007) showed that INM in mice was dependent on the regulation of centrosome-associated microtubules by Cep120 and Taccs (see TACC1; 605301). Cep120 and Taccs regulated the integrity of microtubules coupling the centrosome and the nucleus. Cep120 interacted with Taccs and regulated the localization of Tacc3 (605303) to the centrosome. Both Cep120 and Taccs were essential for maintaining the neural progenitor pool during mouse neocortical development.
Using gene tagging on BACs, protein localization, and tandem-affinity purification-mass spectrometry, Hutchins et al. (2010) showed that CEP120 clustered with proteins required for centriole duplication. RNA interference experiments confirmed that CEP120 was required for centriole duplication. CEP120 also interacted with CCDC52 (SPICE1; 613447).
Mouse tracheal epithelial cells (MTECs) develop cilia when cultured at an air-liquid interface. Mahjoub et al. (2010) found that Cep120 expression peaked with centriole amplification prior to ciliogenesis in MTECs. Deletion analysis revealed that the C-terminal coiled-coil domain of Cep120 was required for centriole localization. Knockdown of Cep120 in mouse embryonic fibroblasts via short hairpin RNA had no effect on cell cycle progression or cell division, but it interfered with centriole duplication. In MTECs, knockdown of Cep120 caused failure to assemble centrioles and cilia. Formation of a daughter centriole was a prerequisite for reduction in Cep120 content and acquisition of appendages by mother centrioles.
Using immunoprecipitation analysis and protein pull-down assays, Lin et al. (2013) found that CEP120 interacted with CPAP (CENPJ; 609279) in human cell lines. Overexpression of either protein caused formation of supernumerary centrioles and extra long and abnormally branched microtubule-based filaments that extended from elongated centrioles. Depletion of CEP120 or CPAP in U2OS cells reduced centriolar targeting of the other protein. Deletion analysis of CEP120 identified an N-terminal microtubule-binding domain, a central CPAP-interacting domain, and a C-terminal dimerization domain that overlapped the centriole-localization domain within the coiled-coil region. The microtubule-binding region of CEP120 was essential for its centriole-elongating activity.
Comartin et al. (2013) found that CEP120 interacted with both SPICE1 and CPAP, and that all 3 proteins were required for centriole elongation and for recruitment of distal microtubule-capping proteins and CEP135 (611423) to procentrioles.
Short-Rib Thoracic Dysplasia 13
In 4 unrelated infants with short-rib thoracic dysplasia and polydactyly (SRTD13; 616300), who all died within the first week of life due to respiratory insufficiency, Shaheen et al. (2015) identified homozygosity for a missense mutation in the CEP120 gene (A199P; 613446.0001). Patient fibroblasts showed marked reduction of cilia and an abnormal number of centrioles compared to controls.
In a male fetus of Flemish origin (SW-476410) exhibiting SRTD without polydactyly and with neurologic features including the molar tooth sign, Roosing et al. (2016) identified compound heterozygosity for the previously reported A199P mutation and a nonsense mutation in the CEP120 gene (R151X; 613446.0002). In another male fetus of Turkish origin (MKS-2930) showing SRTD with polydactyly, Roosing et al. (2016) identified homozygosity for a missense mutation in CEP120 (I949S; 613446.0003).
Joubert Syndrome 31
In 4 patients with Joubert syndrome (JBTS31; 617761), with ages ranging from 2 to 11 years, Roosing et al. (2016) identified homozygous or compound heterozygous mutations in the CEP120 gene (see, e.g., 613446.0004-613446.0008). Noting that all 4 patients had a relatively mild, purely neurologic phenotype, whereas other patients with mutations in CEP120 exhibit a more complex and severe phenotype, Roosing et al. (2016) stated that the mechanism through which mutations in the same gene cause such wide phenotypic variability remained unexplained.
Shaheen et al. (2015) performed knockdown of the zebrafish CEP120 analog and observed a typical ciliopathy phenotype with ventrally curved body axis, hydrocephalus, otolith defects, cardiac edema, and smaller eyes at 3 days postfertilization (dpf) compared to controls. Embryos that survived to 4 dpf developed pronephric duct dilatation, glomerular cysts, and severe general edema. Alcian-Blue staining revealed striking craniofacial defects, with most of the craniofacial cartilage missing. Immunofluorescence imaging using confocal microscopy showed disorganized cilia in the pronephric duct and shorter cilia in the neural tube, but no significant reduction in the number of cilia was observed.
In 4 unrelated infants, including 2 of Saudi Arabian origin and 1 of Swiss ancestry, who had short-rib thoracic dysplasia-13 with or without polydactyly (SRTD13; 616300), Shaheen et al. (2015) identified homozygosity for a c.595G-C transversion (c.595G-C, NM_153223.3) in exon 6 of the CEP120 gene, resulting in an ala199-to-pro (A199P) substitution at a highly conserved residue within the MT-binding domain. The variant, which was present in heterozygous state in 1 of 1,294 Saudi alleles tested and in 2 of 12,000 alleles in the Exome Variant Server database, was not found in the 1000 Genomes Project database. Patient fibroblasts showed a dramatic reduction in the frequency of ciliated cells compared to controls: control fibroblast cells consistently showed a single centrosome after 24 hours of serum starvation to induce ciliogenesis, but approximately half of patient fibroblasts showed a variable number of centrosomes, ranging from 1 to more than 4. All 4 affected infants died of respiratory failure within the first week of life. Haplotype analysis of the 2 Saudi families and the Swiss family showed shared runs of homozygosity of 714,139 bp, indicating that the mutation originated from a common founder and was most likely very ancient.
In a male fetus of Flemish origin (SW-476410) exhibiting SRTD without polydactyly and also showing central nervous system malformations including suboccipital encephalocele, dysplastic tectum, enlarged posterior fossa, severe hypoplasia of the cerebellar vermis, and molar tooth sign on fetal MRI, Roosing et al. (2016) identified compound heterozygosity for the A199P mutation and a c.451C-T transition in exon 5 of the CEP120 gene, resulting in an arg151-to-ter (R151X; 613446.0002) substitution within the C2 domain. The unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in a combined in-house database; in addition, the nonsense mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases.
For discussion of the c.451C-T transition (c.451C-T, NM_153223.3) in exon 5 of the CEP120 gene, resulting in an arg151-to-ter (R151X) substitution, that was found in compound heterozygous state in a male fetus of Flemish origin (SW-476410) with short-rib thoracic dysplasia without polydactyly (SRTD13; 616300) by Roosing et al. (2016), see 613446.0001.
In a male fetus of Turkish origin (MKS-2930) with short-rib thoracic dysplasia and preaxial and postaxial polydactyly (SRTD13; 616300) as well as cystic dysplastic kidneys and central nervous system malformations including occipital encephalocele and enlarged posterior fossa, Roosing et al. (2016) identified homozygosity for a c.2924T-G transversion (c.2924T-G, NM_153223.3) in exon 21 of the CEP120 gene, resulting in an ile949-to-ser (I949S) substitution at a highly conserved residue within the coiled-coil domain. The mutation was present in heterozygosity in the unaffected consanguineous parents, but was not found in a combined in-house database or in the dbSNP, Exome Variant Server, or ExAC databases.
In a 4.5-year-old Italian girl (COR391) with Joubert syndrome (JBTS31; 617761), Roosing et al. (2016) identified homozygosity for a c.581T-C transition (c.581T-C, NM_153223.3) in exon 6 of the CEP120 gene, resulting in a val194-to-ala (V194A) substitution at a highly conserved residue. The mutation was present in heterozygosity in her unaffected consanguineous parents, but was not found in a combined in-house database or in the dbSNP, Exome Variant Server, or ExAC databases.
In an 11-year-old boy from the United States (MTI-143) with Joubert syndrome (JBTS31; 617761), Roosing et al. (2016) identified compound heterozygosity for 2 missense mutations in the CEP120 gene: a c.2134C-T transition (c.2134C-T, NM_153223.3), resulting in a leu712-to-phe (L712F) substitution, and a c.2177T-C transition, resulting in a leu726-to-pro (L726P; 613446.0006) substitution. Both mutations occurred in exon 16 and involved highly conserved residues. The mutations segregated fully with disease in the family, and neither was found in a combined in-house database. The L726P mutation was not found in the dbSNP, Exome Variant Server (EVS), or ExAC databases, whereas the L712F variant was present in dbSNP (rs114280473) as well as in the EVS and ExAC databases at very low frequency, but never in homozygous state.
For discussion of the c.2177T-C transition (c.2177T-C, NM_153223.3) in exon 16 of the CEP120 gene, resulting in a leu726-to-pro (L726P) substitution, that was found in compound heterozygous state in an 11-year-old boy from the United States (MTI-143) with Joubert syndrome (JBTS31; 617761) by Roosing et al. (2016), see 613446.0005.
In a 2-year-old Indian girl (MTI-1516) with Joubert syndrome (JBTS31; 617761), Roosing et al. (2016) identified compound heterozygosity for 2 mutations in the CEP120 gene: a 1-bp insertion (c.1138_1139insA, NM_153223.3) in exon 9, causing a frameshift predicted to result in a premature termination codon (Ser380ThrfsTer19), and a c.1646C-T transition in exon 12, resulting in an ala549-to-val (A549V; 613446.0008) substitution at a highly conserved residue. Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in a combined in-house database or in the dbSNP, Exome Variant Server, or ExAC databases.
For discussion of the c.1646C-T transition (c.1646C-T, NM_153223.3) in exon 12 of the CEP120 gene, resulting in an ala549-to-val (A549V) substitution, that was found in compound heterozygous state in 2-year-old Indian girl (MTI-1516) with Joubert syndrome (JBTS31; 617761) by Roosing et al. (2016), see 613446.0007.
Comartin, D., Gupta, G. D., Fussner, E., Coyaud, E., Hasegan, M., Archinti, M., Cheung, S. W. T., Pinchev, D., Lawo, S., Raught, B., Bazett-Jones, D. P., Luders, J., Pelletier, L. CEP120 and SPICE1 cooperate with CPAP in centriole elongation. Curr. Biol. 23: 1360-1366, 2013. [PubMed: 23810536] [Full Text: https://doi.org/10.1016/j.cub.2013.06.002]
Hartz, P. A. Personal Communication. Baltimore, Md. 6/11/2010.
Hutchins, J. R. A., Toyoda, Y., Hegemann, B., Poser, I., Heriche, J.-K., Sykora, M. M., Augsburg, M., Hudecz, O., Buschhorn, B. A., Bulkescher, J., Conrad, C., Comartin, D., and 18 others. Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science 328: 593-599, 2010. [PubMed: 20360068] [Full Text: https://doi.org/10.1126/science.1181348]
Lin, Y.-N., Wu, C.-T., Lin, Y.-C., Hsu, W.-B., Tang, C.-J. C., Chang, C.-W., Tang, T. K. CEP120 interacts with CPAP and positively regulates centriole elongation. J. Cell Biol. 202: 211-219, 2013. [PubMed: 23857771] [Full Text: https://doi.org/10.1083/jcb.201212060]
Mahjoub, M. R., Xie, Z., Stearns, T. Cep120 is asymmetrically localized to the daughter centriole and is essential for centriole assembly. J. Cell Biol. 191: 331-346, 2010. [PubMed: 20956381] [Full Text: https://doi.org/10.1083/jcb.201003009]
Roosing, S., Romani, M., Isrie, M., Rosti, R. O., Micalizzi, A., Musaev, D., Mazza, T., Al-gazali, L., Altunoglu, U., Boltshauser, E., D'Arrigo, S., De Keersmaeker, B., and 12 others. Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. J. Med. Genet. 53: 608-615, 2016. [PubMed: 27208211] [Full Text: https://doi.org/10.1136/jmedgenet-2016-103832]
Shaheen, R., Schmidts, M., Faqeih, E., Hashem, A., Lausch, E., Holder, I., Superti-Furga, A., UK10K Consortium, Mitchison, H. M., Almoisheer, A., Alamro, R., Alshiddi, T., Alzahrani, F., Beales, P. L., Alkuraya, F. S. A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies. Hum. Molec. Genet. 24: 1410-1419, 2015. [PubMed: 25361962] [Full Text: https://doi.org/10.1093/hmg/ddu555]
Xie, Z., Moy, L. Y., Sanada, K., Zhou, Y., Buchman, J. J., Tsai, L.-H. Cep120 and TACCs control interkinetic nuclear migration and the neural progenitor pool. Neuron 56: 79-93, 2007. [PubMed: 17920017] [Full Text: https://doi.org/10.1016/j.neuron.2007.08.026]