Alternative titles; symbols
HGNC Approved Gene Symbol: NCAPH
Cytogenetic location: 2q11.2 Genomic coordinates (GRCh38): 2:96,335,766-96,377,091 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q11.2 | ?Microcephaly 23, primary, autosomal recessive | 617985 | Autosomal recessive | 3 |
Bhat et al. (1996) established that in Drosophila the product of 'barr' (barren) is necessary for sister chromatid separation and modulates topoisomerase II (126430) activity. The barr gene is evolutionarily conserved and sequence similarity searches identified a 2.7-kb human homolog.
Cabello et al. (1997) reported the genomic localization of this human member of the barr gene family, symbolized BRRN1 by them. By Southern analysis of monochromosomal human/rodent hybrid cells, they mapped the BRRN1 gene to chromosome 2. By fluorescence in situ hybridization, they localized the assignment to 2q11.2. This assignment was confirmed and refined by radiation hybrid analysis.
Aono et al. (2002) reported that Cnd2, the fission yeast homolog of Drosophila barren and the budding yeast protein Brn1, is required for both interphase and mitotic condensation. In Cnd2 mutants, ultraviolet-induced DNA damage was not repaired and cells arrested by hydroxyurea did not recover. Cds1 (604373) activation was abolished in the presence of hydroxyurea in Cnd2 mutant cells and in cells where other condensin subunits had been disrupted. In the absence of hydroxyurea, a G2 checkpoint delay occurred in Cnd2 mutants in a manner dependent on Cds1 and Rad3 but not Chk1 (603078), before the mitotic condensation defect. Furthermore, the Cnd2 mutation was synthetic-lethal with mutations of excision repair, RecQ helicase (see 600537), and DNA replication enzymes.
In a 42-year-old man of Portuguese descent (P3) with autosomal recessive primary microcephaly-23 (MCPH23; 617985), Martin et al. (2016) identified a homozygous missense mutation in the NCAPH gene (P243L; 602332.0001). The mutation, which was found by screening of a panel of genes involved in the condensin I and II complexes in 198 patients with microcephaly, was confirmed by Sanger sequencing and segregated with the disorder in the family. Patient fibroblasts showed impaired chromosome segregation and abnormal recovery from mitotic condensation compared to controls, consistent with decatenation failure at mitosis. These abnormalities could potentially reduce neuronal cell proliferation, viability, and survival, resulting in microcephaly. The findings suggested that the mutation disrupted condensin-dependent mitotic chromosome integrity.
In a 42-year-old man of Portuguese descent (P3) with autosomal recessive primary microcephaly-23 (MCPH23; 617985), Martin et al. (2016) identified a homozygous c.728C-T transition in the NCAPH gene, resulting in a pro243-to-leu (P243L) substitution at a highly conserved residue. The mutation, which was found by screening of a panel of genes involved in the condensin I and II complexes, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the ExAC database. Patient cells showed normal levels of the mutant protein.
Aono, N., Sutani, T., Tomonaga, T., Mochida, S., Yanagida, M. Cnd2 has dual roles in mitotic condensation and interphase. Nature 417: 197-202, 2002. [PubMed: 12000964] [Full Text: https://doi.org/10.1038/417197a]
Bhat, M. A., Philp, A. V., Glover, D. M., Bellen, H. J. Chromatid segregation at anaphase requires the barren product, a novel chromosome-associated protein that interacts with topoisomerase II. Cell 87: 1103-1114, 1996. [PubMed: 8978614] [Full Text: https://doi.org/10.1016/s0092-8674(00)81804-8]
Cabello, O. A., Baldini, A., Bhat, M., Bellen, H., Belmont, J. W. Localization of BRRN1, the human homologue of Drosophila barr, to 2q11.2. Genomics 46: 311-313, 1997. [PubMed: 9417923] [Full Text: https://doi.org/10.1006/geno.1997.5021]
Martin, C.-A., Murray, J. E., Carroll, P., Leitch, A., Mackenzie, K. J., Halachev, M., Fetit, A. E., Keith, C., Bicknell, L. S., Fluteau, A., Gautier, P., Hall, E. A., and 12 others. Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis. Genes Dev. 30: 2158-2172, 2016. Note: Erratum: Genes Dev. 31: 953 only, 2017. [PubMed: 27737959] [Full Text: https://doi.org/10.1101/gad.286351.116]