Alternative titles; symbols
HGNC Approved Gene Symbol: NCAPG2
Cytogenetic location: 7q36.3 Genomic coordinates (GRCh38) : 7:158,631,169-158,704,804 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q36.3 | Khan-Khan-Katsanis syndrome | 618460 | Autosomal recessive | 3 |
Condensin complexes I and II play essential roles in mitotic chromosome assembly and segregation. Both condensins contain 2 invariant structural maintenance of chromosome (SMC) subunits, SMC2 (605576) and SMC4 (605575), but they contain different sets of non-SMC subunits. NCAPG2 is 1 of 3 non-SMC subunits that define condensin II (Ono et al., 2003). Condensin II typically localizes to the nucleus and binds chromatin during early condensation in prophase (summary by Khan et al., 2019).
Ono et al. (2003) immunoprecipitated the condensin II complex from HeLa cell nuclear extracts and identified NCAPG2, which they called CAPG2, among its subunits. The 1,143-amino acid CAPG2 protein contains 5 HEAT repeats. SDS-PAGE showed that CAPG2 had an apparent molecular mass of 125 kD.
Smith et al. (2004) isolated mouse Mtb in a yeast 2-hybrid screen for Scl (187040)-interacting proteins and cloned the full-length cDNA. The deduced 849-amino acid protein shows weak homology to a leucine zipper motif and harbors several putative phosphorylation sites. Smith et al. (2004) identified NCAPG2 as the human homolog of Mtb and determined that the proteins share 80% identity. Northern blot analysis of mouse embryos and tissues detected 2 transcripts that differed in the 5-prime and 3-prime UTRs. Whole-mount in situ hybridization demonstrated wide expression during early embryonic development and more restricted expression during later developmental stages. In adult mice, Mtb was expressed in spleen, lung, and testis, as well as in all hematopoietic cell lines tested.
By sucrose gradient centrifugation of HeLa cell nuclear extracts and Western blot analysis, Ono et al. (2003) found that the condensin II-specific subunits CAPH2 (NCAPH2; 611230), CAPD3 (NCAPD3; 609276), and CAPG2 comigrated at about 13.5S. Immunofluorescence analysis of HeLa cells with anti-CAPG2 antibodies showed that condensins I and II had different distributions along metaphase chromosomes. Depletion of CAPG2 from HeLa cells or Xenopus egg extracts altered the shape of mitotic chromosomes, implying that CAPG2 has a role in maintaining the physical rigidity of the chromatid axis.
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 MTB. 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.
Hartz (2004) mapped the MTB gene to chromosome 7q36.3 based on an alignment of the MTB sequence (GenBank AK000318) with the genomic sequence.
In 2 unrelated girls with Khan-Khan-Katsanis syndrome (3KS; 618460), Khan et al. (2019) identified homozygous or compound heterozygous missense mutations in the NCAPG2 gene (608532.0001-608532.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Lymphocytes derived from 1 of the patients showed normal NCAPG2 protein levels, and patient-derived fibroblasts showed normal localization of NCAPG2 to the nucleus. However, patient fibroblasts showed increased apoptosis with a 6-fold increase in cell death compared to controls. This was associated with multiple abnormalities during mitosis, including impaired chromosomal condensation, lagging chromatin fragments and chromatin bridges, and increased numbers of micronuclei compared to controls. Cell cycle studies revealed increased G2/M arrest in patient cells. Expression of the mutations was unable to rescue the decreased head size or renal defects in zebrafish with knockdown of the ncapg2 gene, suggesting that all variants resulted in a loss of function.
Smith et al. (2004) found that targeted disruption of Mtb in mice resulted in embryos that died immediately following implantation. The lethality was due to a defect in expansion of the inner cell mass, as Mtb null blastocysts failed to exhibit outgrowth of the inner cell mass both in vitro and in vivo. Furthermore, Mtb null blastocysts exhibited a higher frequency of apoptotic cells than wildtype or heterozygous blastocysts.
Khan et al. (2019) found that knockdown of the ncapg2 gene in zebrafish, using both morpholino knockdown and CRISPR/Cas9 genome editing, resulted in a dose-dependent significant reduction in head size and anterior brain structures compared to controls. These defects were associated with altered cell cycle progression and increased apoptosis. In addition, mutant animals showed several renal abnormalities, including renal aplasia, hypoplastic renal tubules, and enlarged renal tubule diameter compared to controls. The abnormalities could be rescued by expression of wildtype human NCAPG2.
El Yakoubi and Akera (2023) noted that female hybrid mice from 2 different species, domesticus and spretus, are subfertile due to chromosome segregation errors in meiosis I and aneuploid eggs. They found that hybrid oocytes displayed chromosome condensation defects with domesticus centromeres stretching, leading to chromosome missegregation during meiosis. Egg aneuploidy was caused by misregulation of the condensin II complex in hybrid oocytes. Condensin II subunit Ncapg2 localized in nuclei of domesticus oocytes for timely chromosome condensation in metaphase. Compared with domesticus oocytes, nuclear localization of Ncapg2 was lower, with significantly shorter and wider chromosomes. Hybrid oocytes inherited the reduced condensin II trait from the spretus parent with reduced nuclear localization of Ncapg2, but they inherited major satellites from the domesticus parent. As a result, less condensin II complex was enriched on metaphase chromosomes, resulting in less condensed domesticus chromosomes with stretched centromeres. Less nuclear Ncapg2 also reduced the condensin II levels at major satellites locally, which caused major satellites to stretch through Top2a (126430), resulting in further reduction of overall condensin II levels and further domesticus centromere stretching. The condensation difference of chromosomes from 2 difference species led to incompatibilities in hybrid of oocytes, affecting the chromosome segregation in meiosis and female fertility, thereby maintaining reproductive isolation between the different species. Analysis of condensin II levels in other mouse species and 2 additional hybrid mice confirmed the reproductive isolating barrier between species established by major satellites and condensin II abundance.
In an 11-year-old girl, born of unrelated European American parents (family 1) with Khan-Khan-Katsanis syndrome (3KS; 618460), Khan et al. (2019) identified compound heterozygous missense mutations in the NCAPG2 gene: a c.1825A-G transition (c.1825A-G, NM_017760.6), resulting in a lys609-to-glu (K609E) substitution, and a c.2078C-T transition, resulting in a thr693-to-met (T693M; 608532.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The K609E variant was not found in the gnomAD database, whereas T693M was found at a low frequency (7 of 245,490 alleles). Patient-derived lymphocytes showed normal NCAPG2 protein levels, and patient-derived fibroblasts showed normal localization of NCAPG2 to the nucleus. However, patient fibroblasts showed increased apoptosis with a 6-fold increase in cell death compared to controls. This was associated with multiple abnormalities during mitosis, including impaired chromosomal condensation, lagging chromatin fragments and chromatin bridges, and increased numbers of micronuclei compared to controls. Cell cycle studies revealed increased G2/M arrest in patient cells. Expression of each mutation was unable to rescue the decreased head size or renal defects in zebrafish with knockdown of the ncapg2 gene, suggesting that both variants resulted in a loss of function, although T693M acted more as a hypomorph. This patient also carried a paternally-inherited heterozygous deletion that encompassed the NPHP1 gene (607100), which may have contributed to the phenotype.
For discussion of the c.2078C-T transition (c.2078C-T, NM_017760.6) in the NCAPG2 gene, resulting in a thr693-to-met (T693M) substitution, that was found in compound heterozygous state in a patient with Khan-Khan-Katsanis syndrome (3KS; 618460) by Khan et al. (2019), see 608532.0001.
In a girl, born of Mexican parents (family 2), with Khan-Khan-Katsanis syndrome (3KS; 618460), Khan et al. (2019) identified a homozygous c.2548A-C transversion (c.2548A-C, NM_017760.6) in the NCAPG2 gene, resulting in a thr850-to-pro (T850P) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the gnomAD database. Functional studies of patient cells were not performed, but expression of the mutation was unable to rescue the decreased head size or renal defects in zebrafish with knockdown of the ncapg2 gene, suggesting that the variant resulted in a loss of function.
El Yakoubi, W., Akera, T. Condensin dysfunction is a reproductive isolating barrier in mice. Nature 623: 347-355, 2023. [PubMed: 37914934] [Full Text: https://doi.org/10.1038/s41586-023-06700-6]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/16/2004.
Khan, T. N., Khan, K., Sadeghpour, A., Reynolds, H., Perilla, Y., McDonald, M. T., Gallentine, W. B., Baig, S. M., Task Force for Neonatal Genomics, Davis, E. E., Katsanis, N. Mutations in NCAPG2 cause a severe neurodevelopmental syndrome that expands the phenotypic spectrum of condensinopathies. Am. J. Hum. Genet. 104: 94-111, 2019. [PubMed: 30609410] [Full Text: https://doi.org/10.1016/j.ajhg.2018.11.017]
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]
Ono, T., Losada, A., Hirano, M., Myers, M. P., Neuwald, A. F., Hirano, T. Differential contributions of condensin I and condensin II to mitotic chromosome architecture in vertebrate cells. Cell 115: 109-121, 2003. [PubMed: 14532007] [Full Text: https://doi.org/10.1016/s0092-8674(03)00724-4]
Smith, E. D., Xu, Y., Tomson, B. N., Leung, C. G., Fujiwara, Y., Orkin, S. H., Crispino, J. D. More than blood, a novel gene required for mammalian postimplantation development. Molec. Cell. Biol. 24: 1168-1173, 2004. [PubMed: 14729962] [Full Text: https://doi.org/10.1128/MCB.24.3.1168-1173.2004]