Alternative titles; symbols
HGNC Approved Gene Symbol: CENPE
Cytogenetic location: 4q24 Genomic coordinates (GRCh38): 4:103,105,811-103,198,343 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q24 | ?Microcephaly 13, primary, autosomal recessive | 616051 | Autosomal recessive | 3 |
The CENPE gene encodes a large kinetochore-associated kinesin-like motor protein required for spindle microtubule capture and attachment at the kinetochore during cell division (summary by Mirzaa et al., 2014).
Yen et al. (1991) identified a 250- to 300-kD human centromere-associated protein, CENPE, by preparing monoclonal antibodies against a fraction of HeLa chromosome scaffold proteins enriched for centromere/kinetochore components. In cells progressing through different parts of the cell cycle, the localization of CENPE differs markedly from that observed for the previously identified centromere proteins CENPA (117139), CENPB (117140), and CENPC (117141). In contrast to these antigens, no monoclonal antibody staining was detected during interphase, and staining first appeared at the centromere region of chromosomes during prometaphase. Microinjection of the monoclonal antibody 177, which demonstrated CENPE, into metaphase cells blocked or significantly delayed progression into anaphase, although the morphology of the spindle and the configuration of the metaphase chromosomes appeared normal in these metaphase-arrested cells. Thus, CENPE function is required for the transition from metaphase to anaphase.
Testa et al. (1994) used CENPE cDNA to map the human gene to chromosome 4q24-q25 by fluorescence in situ hybridization.
Gross (2014) mapped the CENPE gene to chromosome 4q24 based on an alignment of the CENPE sequence (GenBank AB209996) with the genomic sequence (GRCh38).
Lawrence et al. (2004) presented a standardized kinesin nomenclature based on 14 family designations. Under this system, CENPE, or KIF10, belongs to the kinesin-7 family.
Yen et al. (1992) identified CENPE as a kinesin-like motor protein (Mr 312,000) that accumulates in the G2 phase of the cell cycle. CENPE associates with kinetochores during congression, relocates to the spindle midzone at anaphase, and is quantitatively discarded at the end of the cell division. CENPE is probably one of the motors responsible for mammalian chromosome movement and/or spindle elongation.
Wood et al. (1997) cloned the Xenopus CENPE, which shows 74% identity with the human homolog. This protein associates with Xenopus centromeres in vivo and in vitro, and is required for metaphase chromosome alignment. Addition of anti-Xenopus CENPE antibodies disrupts metaphase chromosome alignment. Wood et al. (1997) further demonstrated that Xenopus CENPE powers chromosome movement towards microtubule plus ends in vitro. These data support a model in which CENPE functions in congression to tether kinetochores to microtubule plus ends.
Yao et al. (2000) investigated the function of CENPE in attachment of kinetochores to spindle microtubules, alignment of chromosomes, and checkpoint signaling, using antisense oligonucleotides to suppress its synthesis and accumulation. They showed that CENPE is essential for stable, bioriented attachment of chromosomes to spindle microtubules, for development of tension across aligned chromosomes, for stabilization of spindle poles, and for satisfying the mitotic checkpoint.
Using Xenopus egg extracts, Abrieu et al. (2000) found that CENPE is required for establishing and maintaining a checkpoint that delays anaphase onset until all centromeres are correctly attached to the mitotic spindle. When CENPE function was disrupted by immunodepletion or antibody addition, extracts failed to arrest in response to spindle damage. Mitotic arrest could be restored by addition of high levels of soluble MAD2 (601467), demonstrating that the absence of CENPE eliminates kinetochore-dependent signaling but not the downstream steps in checkpoint signal transduction. Because it directly bound both to spindle microtubules and to the kinetochore-associated checkpoint kinase BUBR1 (602860), the authors concluded that CENPE is a central component in the vertebrate checkpoint that modulates signaling activity in a microtubule-dependent manner.
Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was CENPE. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown.
Spiliotis et al. (2005) showed that defects resulting from septin (see 604061) depletion correlated with the loss of the mitotic motor and CENPE from the kinetochores of congressing chromosomes. The authors suggested that mammalian septins may form a mitotic scaffold for CENPE and other effectors to coordinate cytokinesis with chromosome congression and segregation.
CENPE is a microtubule plus-end-directed kinetochore motor required for congression of pole-proximal chromosomes. Barisic et al. (2015) found that congression of pole-proximal chromosomes depended on specific posttranslational detyrosination of spindle microtubules that point to the equator. In vitro reconstitution experiments demonstrated that CENPE-dependent transport was strongly enhanced on detyrosinated microtubules. Blocking tubulin tyrosination in cells caused ubiquitous detyrosination of spindle microtubules, and CENPE transported chromosomes away from spindle poles in random directions. Thus, Barisic et al. (2015) concluded that CENPE-driven chromosome congression is guided by microtubule detyrosination.
In a brother and sister, born of unrelated parents of European descent, with autosomal recessive primary microcephaly-13 (MCPH13; 616051), Mirzaa et al. (2014) identified compound heterozygous missense mutations in the CENPE gene (D933N, 117143.0001 and K1355E, 117143.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Studies of patient cells as well as cells transfected with the mutations demonstrated abnormalities in spindle microtubule organization and mitotic progression.
Putkey et al. (2002) found that Cenpe deletion in mice caused early embryonic lethality, with embryos unable to implant or develop past implantation. Conditional Cenpe disruption in cultured mouse embryonic fibroblasts and in regenerating adult liver following chemical injury led to abnormalities in chromosome alignment during cell division. Most Cenpe-null chromosomes moved to the spindle equator in metaphase, but their kinetochores bound only half the normal number of microtubules. Some metaphase chromosomes were near spindle poles. Putkey et al. (2002) concluded that CENPE is essential for the maintenance of chromosome stability through efficient stabilization of microtubule capture at kinetochores.
In a brother and sister, born of unrelated parents of European descent, with autosomal recessive primary microcephaly-13 (MCPH13; 616051), Mirzaa et al. (2014) identified compound heterozygous mutations in the CENPE gene: a c.2797G-A transition, resulting in an asp933-to-asn (D933N) substitution, and a c.4063A-G transition, resulting in a lys1355-to-glu (K1355E; 117143.0002) substitution. Both mutations occurred in the alpha-helical coiled-coil region. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants were present in the dbSNP and Exome Variant Server databases, but at a very low frequency (1 in 8,597 for D933N and 3 in 8,595 for K1355E) that did not rule out their involvement in an autosomal recessive developmental disorder. The substitutions occurred at relatively conserved residues in mammals, although not in the mouse. Patient mitotic lymphocytes showed reduced centromeric accumulation of mutant CENPE and altered spindle dynamics with lagging chromosomes as well as a disorganized spindle network structure compared to control cells. Cellular transfection of the mutations induced mitotic spindle abnormalities and polar chromosomes both independently and when expressed together. Patient cells and transfected cells also showed delayed mitotic progression. Mirzaa et al. (2014) noted that some of the cellular defects associated with these CENPE mutations were similar to those of cells with mutations in the PCNT gene (605925), which is mutated in microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720), a disorder with some overlapping features.
For discussion of the lys1355-to-glu (K1355E) mutation in the CENPE gene that was found in compound heterozygous state in patients with autosomal recessive primary microcephaly-13 (MCPH13; 616051) by Mirzaa et al. (2014), see 117143.0001.
Abrieu, A., Kahana, J. A., Wood, K. W., Cleveland, D. W. CENP-E as an essential component of the mitotic checkpoint in vitro. Cell 102: 817-826, 2000. [PubMed: 11030625] [Full Text: https://doi.org/10.1016/s0092-8674(00)00070-2]
Barisic, M., Silva e Sousa, R., Tripathy, S. K., Magiera, M. M., Zaytsev, A. V., Pereira, A. L., Janke, C., Grishchuk, E. L., Maiato, H. Microtubule detyrosination guides chromosomes during mitosis. Science 348: 799-803, 2015. [PubMed: 25908662] [Full Text: https://doi.org/10.1126/science.aaa5175]
Gross, M. B. Personal Communication. Baltimore, Md. 11/4/2014.
Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F. An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division. Nature 432: 1036-1040, 2004. [PubMed: 15616564] [Full Text: https://doi.org/10.1038/nature03159]
Lawrence, C. J., Dawe, R. K., Christie, K. R., Cleveland, D. W., Dawson, S. C., Endow, S. A., Goldstein, L. S. B., Goodson, H. V., Hirokawa, N., Howard, J., Malmberg, R. L., McIntosh, J. R., and 10 others. A standardized kinesin nomenclature. J. Cell Biol. 167: 19-22, 2004. [PubMed: 15479732] [Full Text: https://doi.org/10.1083/jcb.200408113]
Mirzaa, G. M., Vitre, B., Carpenter, G., Abramowicz, I., Gleeson, J. G., Paciorkowski, A. R., Cleveland, D. W., Dobyns, W. B., O'Driscoll, M. Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Hum. Genet. 133: 1023-1039, 2014. [PubMed: 24748105] [Full Text: https://doi.org/10.1007/s00439-014-1443-3]
Putkey, F. R., Cramer, T., Morphew, M. K., Silk, A. D., Johnson, R. S., McIntosh, J. R., Cleveland, D. W. Unstable kinetochore-microtubule capture and chromosomal instability following deletion of CENP-E. Dev. Cell 3: 351-365, 2002. [PubMed: 12361599] [Full Text: https://doi.org/10.1016/s1534-5807(02)00255-1]
Spiliotis, E. T., Kinoshita, M., Nelson, W. J. A mitotic septin scaffold required for mammalian chromosome congression and segregation. Science 307: 1781-1785, 2005. [PubMed: 15774761] [Full Text: https://doi.org/10.1126/science.1106823]
Testa, J. R., Zhou, J., Bell, D. W., Yen, T. J. Chromosomal localization of the genes encoding the kinetochore proteins CENPE and CENPF to human chromosomes 4q24-q25 and 1q32-q41, respectively, by fluorescence in situ hybridization. Genomics 23: 691-693, 1994. [PubMed: 7851898] [Full Text: https://doi.org/10.1006/geno.1994.1558]
Wood, K. W., Sakowicz, R., Goldstein, L. S. B., Cleveland, D. W. CENP-E is a plus end-directed kinetochore motor required for metaphase chromosome alignment. Cell 91: 357-366, 1997. [PubMed: 9363944] [Full Text: https://doi.org/10.1016/s0092-8674(00)80419-5]
Yao, X., Abrieu, A., Zheng, Y., Sullivan, K. F., Cleveland, D. W. CENP-E forms a link between attachment of spindle microtubules to kinetochores and the mitotic checkpoint. Nature Cell Biol. 2: 484-491, 2000. [PubMed: 10934468] [Full Text: https://doi.org/10.1038/35019518]
Yen, T. J., Compton, D. A., Wise, D., Zinkowski, R. P., Brinkley, B. R., Earnshaw, W. C., Cleveland, D. W. CENP-E, a novel human centromere-associated protein required for progression from metaphase to anaphase. EMBO J. 10: 1245-1254, 1991. [PubMed: 2022189] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb08066.x]
Yen, T. J., Li, G., Schaar, B. T., Szilak, I., Cleveland, D. W. CENP-E is a putative kinetochore motor that accumulates just before mitosis. Nature 359: 536-539, 1992. [PubMed: 1406971] [Full Text: https://doi.org/10.1038/359536a0]