Alternative titles; symbols
HGNC Approved Gene Symbol: KIF2A
Cytogenetic location: 5q12.1 Genomic coordinates (GRCh38): 5:62,306,206-62,391,025 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q12.1 | Cortical dysplasia, complex, with other brain malformations 3 | 615411 | Autosomal dominant | 3 |
KIF2A, KIF2B (615142), and KIF2C (604538) comprise the kinesin-13 family of microtubule motor proteins, which are characterized by the localization of the kinesin motor domain in the middle of the polypeptide. Kinesin-13 proteins are nonmotile and induce microtubule depolymerization by disassembling tubulin subunits from the polymer end. KIF2A is essential for both bipolar spindle assembly and chromosome movement (summary by Manning et al., 2007).
For background information on kinesins, see 148760.
By using cDNA differential display, Debernardi et al. (1997) isolated a kinesin heavy chain gene (KIF2) as one regulated by the synthetic retinoid HPR, a cancer chemopreventive agent and inducer of apoptotic cell death. The KIF2 gene, which they called HK2 for 'human kinesin-2,' was cloned from follicular B-cell lymphoma cells treated with HPR. Human KIF2 is a predicted 679-amino acid protein that is 97% identical to mouse KIF2 protein. On Northern blots, KIF2 was expressed as a 3.5-kb mRNA in several tissues.
Using in situ hybridization and immunofluorescence assays, Ruiz-Reig et al. (2022) showed that Kif2a was expressed in postmitotic neurons of mice throughout life and, to a lesser extent, in neural progenitors.
Lawrence et al. (2004) presented a standardized kinesin nomenclature based on 14 family designations. Under this system, KIF2A belongs to the kinesin-13 family.
Debernardi et al. (1997) mapped the KIF2 gene to chromosome 5q12-q13 by PCR of a panel of radiation hybrid clones.
Gross (2013) mapped the KIF2A gene to chromosome 5q12.1 based on an alignment of the KIF2A sequence (GenBank BC031828) with the genomic sequence (GRCh37).
Using RNA interference in human U2OS and RPE cells, Manning et al. (2007) found that each of the kinesin-13 family members has a distinct role during mitosis. MCAK (KIF2C) deficiency resulted in exaggerated astral microtubule length. KIF2A and KIF2B deficiency resulted in similar defects, with delayed progression through mitosis, appearance of monopolar or disorganized spindles, and increased number of binucleated or dead cells. However, knockdown of KIF2B, but not KIF2A, reduced the poleward kinetochore force acting on chromosomes. Knockdown of KIF2B did not disrupt the pole localization of KIF2A or the centromere and spindle localization of MCAK.
In 2 unrelated patients with complex cortical dysplasia with other brain malformations-3 (CDCBM3; 615411), Poirier et al. (2013) identified 2 different de novo heterozygous mutations in the KIF2A gene (H321D, 602591.0001 and S317N, 602591.0002). The first mutation was found by whole-exome sequencing and was not present in several genomic databases, including dbSNP, 1000 Genomes, the Exome Variant Server, and a local Paris Descartes Bioinformatics platform database. The second mutation was found by screening 162 individuals with various malformations of cortical development for variants in kinesin genes. The patients had microcephaly, early-onset epilepsy, and various malformations of cortical development, including agyria, posterior predominant pachygyria, subcortical band heterotopia, and thin corpus callosum. One patient had dysmorphic basal ganglia. Both had severe developmental delay and were bedridden with spastic paraplegia at ages 1 and 4 years, respectively. In vitro functional expression studies showed that the mutations caused abnormal protein folding, resulting in abnormal cellular localization and a loss of protein function. Because KIF2A functions as a dimer, Poirier et al. (2013) postulated a dominant-negative effect. The findings extended the association between microtubule-based cellular processes and proper cortical development.
Homma et al. (2003) found that brains of Kif2a -/- mice showed multiple phenotypes, including aberrant axonal branching due to overextension of collateral branches. In Kif2a -/- growth cones, microtubule-depolymerizing activity decreased. Moreover, many individual microtubules showed abnormal behavior at the Kif2a -/- cell edge. The authors concluded that KIF2A regulates microtubule dynamics at the growth cone edge by depolymerizing microtubules and that it plays an important role in the suppression of collateral branch extension.
Gilet et al. (2020) generated 3 lines of conditional knockin mice heterozygous for the Kif2a H321D mutation and expressing the mutant protein ubiquitously or specifically in neuronal progenitors or postmitotic neurons. The mutant protein showed abnormal subcellular localization in cortices of Kif2a +/H321C mice, but the mice were viable and born within the expected mendelian ratios. However, these mice presented with an underdeveloped appearance and overall smaller size, lower weight, and microcephaly with reduced brain size with neuroanatomic defects, compared with wildtype. Mutant mice exhibited memory deficits, hyperactivity, and increased susceptibility to epilepsy. Immunohistologic analysis revealed that the H321D mutation caused hippocampal heterotopia in adult mice. Analysis of mutant embryos showed that hippocampal heterotopia was predominantly linked to the postmitotic effects of the H321D mutant, as mainly the mouse embryos with conditional expression of Kif2a H321D in postmitotic neurons, but not the other 2 mutant lines, showed cortical layering and neuronal positioning abnormalities. Moreover, the H321D mutant caused increased cell death, but no anomalies in proliferation, during early embryonic stages, especially in embryos expressing the mutant protein in neuronal progenitors, thereby contributing to the microcephaly observed in the mutant mice. A microtubule depolymerization assay in human and mouse embryonic fibroblasts showed that KIF2A H321D affected microtubule dynamics and depolymerization rates.
Ruiz-Reig et al. (2022) found that mice with cortex-specific conditional deletion of Kif2a had normal brain size and number of neurons at birth but exhibited severe premature neurodegeneration. Analysis of cultured hippocampal neurons from Kif2a -/- embryos showed that Kif2a was essential for glutamatergic synapse maintenance and neuronal function. Labeling by in utero electroporation revealed the importance of Kif2a in neuronal connectivity, as conditional knockout mice exhibited wiring abnormalities. Kif2a was also found to regulate neuritogenesis and to be essential for transport of lysosomes. Kif2a expression was maintained in the adult brain, and its deletion in mature neurons was sufficient to cause their loss without affecting neuronal migration. The results indicated that, in addition to and independent of its role in neuronal migration, KIF2A is also required for neuronal maturation, connectivity, and survival.
In a 1-year-old child with complex cortical dysplasia with other brain malformations-3 (CDCBM3; 615411), Poirier et al. (2013) identified a de novo heterozygous c.961C-G transversion in the KIF2A gene, resulting in a his321-to-asp (H321D) substitution at a conserved residue located around the ATP nucleotide-binding pocket in the kinesin motor domain. The mutation was found by whole-exome sequencing and was not found in several genomic databases, including dbSNP, 1000 Genomes, the Exome Variant Server, and a local Paris Descartes Bioinformatics platform database. In vitro functional expression studies in E. coli showed decreased levels of soluble mutant protein in the extract compared to wildtype, suggesting that the mutation caused misfolding and retention of the protein in the insoluble fraction, resulting in decreased levels of functional protein. Overexpression of the mutant protein in COS-7 cells and human fibroblasts resulted in abnormal cellular localization with predominant decoration of microtubules rather than diffuse punctiform cytoplasmic and nuclear distribution as observed for wildtype KIF2A. Because KIF2A functions as a dimer, Poirier et al. (2013) postulated a dominant-negative effect.
In a 4-year-old child with complex cortical dysplasia with other brain malformations-3 (CDCBM3; 615411), Poirier et al. (2013) identified a de novo heterozygous c.950G-A transition in the KIF2A gene, resulting in a ser317-to-asn (S317N) substitution at a conserved residue located around the ATP nucleotide-binding pocket in the kinesin motor domain. In vitro functional expression studies in E. coli showed decreased levels of soluble mutant protein in the extract compared to wildtype, suggesting that the mutation caused misfolding and retention of the protein in the insoluble fraction, resulting in decreased levels of functional protein. Overexpression of the mutant protein in COS-7 cells and human fibroblasts resulted in abnormal cellular localization with predominant decoration of microtubules rather than diffuse punctiform cytoplasmic and nuclear distribution as observed for wildtype KIF2A. Because KIF2A functions as a dimer, Poirier et al. (2013) postulated a dominant-negative effect.
Debernardi, S., Fontanella, E., De Gregorio, L., Pierotti, M. A., Delia, D. Identification of a novel human kinesin-related gene (HK2) by the cDNA differential display technique. Genomics 42: 67-73, 1997. [PubMed: 9177777] [Full Text: https://doi.org/10.1006/geno.1997.4720]
Gilet, J. G., Ivanova, E. L., Trofimova, D., Rudolf, G., Meziane, H., Broix, L., Drouot, N., Courraud, J., Skory, V., Voulleminot, P., Osipenko, M., Bahi-Buisson, N., Yalcin, B., Birling, M. C., Hinckelmann, M. V., Kwok, B. H., Allingham, J. S., Chelly, J. Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny. Hum. Molec. Genet. 29: 766-784, 2020. [PubMed: 31919497] [Full Text: https://doi.org/10.1093/hmg/ddz316]
Gross, M. B. Personal Communication. Baltimore, Md. 9/18/2013.
Homma, N., Takei, Y., Tanaka, Y., Nakata, T., Terada, S., Kikkawa, M., Noda, Y., Hirokawa, N. Kinesin superfamily protein 2A (KIF2A) functions in suppression of collateral branch extension. Cell 114: 229-239, 2003. [PubMed: 12887924] [Full Text: https://doi.org/10.1016/s0092-8674(03)00522-1]
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]
Manning, A. L., Ganem, N. J., Bakhoum, S. F., Wagenbach, M., Wordeman, L., Compton, D. A. The kinesin-13 proteins, Kif2a, Kif2b, and Kif2c/MCAK have distinct roles during mitosis in human cells. Molec. Biol. Cell 18: 2970-2979, 2007. [PubMed: 17538014] [Full Text: https://doi.org/10.1091/mbc.e07-02-0110]
Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., Parrini, E., Valence, S., Saint Pierre, B., Oger, M., Lacombe, D., Genevieve, D., and 23 others. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nature Genet. 45: 639-647, 2013. Note: Erratum: Nature Genet. 45: 962 only, 2013. [PubMed: 23603762] [Full Text: https://doi.org/10.1038/ng.2613]
Ruiz-Reig, N., Chehade, G., Hakanen, J., Aittaleb, M., Wierda, K., De Wit, J., Nguyen, L., Gailly, P., Tissir, F. KIF2A deficiency causes early-onset neurodegeneration. Proc. Nat. Acad. Sci. 119: e2209714119, 2022. [PubMed: 36343267] [Full Text: https://doi.org/10.1073/pnas.2209714119]