HGNC Approved Gene Symbol: CCND2
Cytogenetic location: 12p13.32 Genomic coordinates (GRCh38): 12:4,273,762-4,305,353 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.32 | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 | 615938 | Autosomal dominant | 3 |
Inaba et al. (1992) used murine cDNA clones for 3 cyclin D genes that are normally expressed during the G1 phase of the cell cycle to clone the cognate human genes. Xiong et al. (1992) also reported the cloning of the CCND2 gene.
Using microarray analysis of gene expression signatures, Lossos et al. (2004) studied prediction of prognosis in diffuse large B-cell lymphoma. In a univariate analysis, genes were ranked on the basis of their ability to predict survival; the strongest predictors of longer overall survival were LMO2 (180385), BCL6 (109565), and FN1 (135600), and the strongest predictors of shorter overall survival were CCND2, SCYA3 (182283), and BCL2 (151430). Lossos et al. (2004) developed a multivariate model that was based on the expression of these 6 genes, and validated the model in 2 independent microarray data sets. The model was independent of the International Prognostic Index and added to its predictive power.
Using knockdown and microarray analysis, Jeong et al. (2016) showed that the dominant variant of long intergenic noncoding RNA-598 (LINC00598; 619008) functioned as a transcriptional regulator of various target genes, including CCND2, in HEK293T cells. LINC00598 regulated expression of CCND2 by reducing the binding affinity of FOXO1A (136533), a negative regulator of CCND2, for the CCND2 promoter. Knockdown of LINC00598 in HEK293T cells induced G0-G1 cell cycle arrest and inhibited cell proliferation. Overexpression of CCND2 rescued G1 arrest in LINC00598-knockdown cells, suggesting that LINC00598 regulates cell proliferation through modulation of the G0-G1 checkpoint via transcriptional regulation of CCND2.
By analysis of somatic cell hybrids containing different human chromosomes and by fluorescence in situ hybridization, Inaba et al. (1992) assigned the CCND2 gene to 12p13. (Since the CCND1 gene (168461) is on 11q13, this may be another bit of evidence of the homology of chromosomes 11 and 12.) Xiong et al. (1992) assigned the CCND2 gene to 12p13 by fluorescence in situ hybridization. A pseudogene of CCND2 was mapped to 11q13 by Inaba et al. (1992).
In 12 probands with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-3 (MPPH3; 615938), Mirzaa et al. (2014) identified 7 different heterozygous mutations in the CCND2 gene (123833.0001-123833.0006). The mutations in the first 3 patients were found by whole-exome sequencing; the mutations in 9 additional patients were found by conventional Sanger sequencing. The mutations occurred de novo in all patients from whom parental DNA was available, except for 1 parent who was mosaic for the mutation. All of the mutations either altered conserved residues surrounding thr280, a GSK3B (605004) phosphorylation target necessary for subsequent protein degradation, or truncated the mutation before this phosphorylation site. Transfection of the CCND2 mutations into HEK293 cells resulted in abnormal accumulation of unphosphorylated, degradation-resistant cyclin D2. In utero electroporation of the T280A (123833.0001) or P281R (123833.0005) mutations into mouse embryos resulted in increased numbers of actively dividing cells in the cortical plate compared to wildtype. These phosphodeficient mutants were more effective in promoting mitosis and were associated with decreased exit from the cell cycle compared to wildtype. These changes were associated with expansion of both radial glial cells and intermediate progenitor cells in the developing cortex. Cells from individuals with megalencephaly due to PIK3CA (171834), PIK3R2 (603157), or AKT3 (611223) mutations showed similar CCND2 accumulation, which indicated that activation of the PI3K-AKT pathway resulting in increased CCND2 is a unifying mechanism in these related disorders. The findings were consistent with a gain-of-function effect of the CCND2 mutations, and Mirzaa et al. (2014) suggested that the expansion of neuronal progenitor populations underlies the megalencephaly as well as the polymicrogyria observed in the disorder.
Kim et al. (2000) used Ccnd1 (168461)- and Ccnd2-deficient mice to investigate the role of cyclins in Schwann cell growth. They concluded that neither Ccnd1 nor Ccnd2 is specifically required for the initial growth and maturation of Schwann cells during mouse development.
Kozar et al. (2004) tested the requirement for D-cyclins in mouse development and in proliferation by generating mice lacking all D-cyclins. Ccnd1 -/- Ccnd2 -/- Ccnd3 -/- mice developed until mid/late gestation and died due to heart abnormalities combined with severe anemia. The authors found that D-cyclins were critically required for expansion of hematopoietic stem cells. In contrast, cyclin D-deficient fibroblasts proliferated nearly normally, but showed increased requirement for mitogenic stimulation in cell cycle reentry. Proliferation of Ccnd1 -/- Ccnd2 -/- Ccnd3 -/- cells was resistant to inhibition by p16(INK4a) (600160), but it critically depended on CDK2 (116953). Cells lacking D-cyclins displayed reduced susceptibility to oncogenic transformation.
In 2 unrelated children with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-3 (MPPH3; 615938), Mirzaa et al. (2014) identified a de novo heterozygous c.838A-G transition in the CCND2 gene, resulting in a thr280-to-ala (T280A) substitution at a highly conserved residue. The mutation, which was found in the first patient by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases.
In 2 unrelated children with MPPH3 (615938), Mirzaa et al. (2014) identified a de novo heterozygous c.808A-T transversion in the CCND2 gene, resulting in a lys270-to-ter (K270X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases.
In 3 unrelated children with MPPH3 (615938), Mirzaa et al. (2014) identified a heterozygous c.839C-A transversion in the CCND2 gene, resulting in a thr280-to-asn (T280N) substitution at a highly conserved residue. The mutation occurred de novo in 2 patients; parental DNA was not available for the third patient.
In a fetus with MPPH3 (615938), Mirzaa et al. (2014) identified a de novo heterozygous c.841C-T transition in the CCND2 gene, resulting in a pro281-to-ser (P281S) substitution at a highly conserved residue.
In 2 unrelated patients with MPPH3 (615938), Mirzaa et al. (2014) identified a heterozygous c.842C-G transversion in the CCND2 gene, resulting in a pro281-to-arg (P281R) substitution at a highly conserved residue. The mutation occurred de novo in 1 patient and was not found in the mother of the second patient; paternal DNA from the second patient was not available.
In a 9-year-old boy with MPPH3 (615938), Mirzaa et al. (2014) identified a heterozygous c.842C-T transition in the CCND2 gene, resulting in a pro281-to-leu (P281L) substitution at a highly conserved residue. The patient's mother, who had a large head, hypertelorism, and borderline intelligence, appeared to be mosaic for the mutation based on blood and saliva studies.
Inaba, T., Matsushime, H., Valentine, M., Roussel, M. F., Sherr, C. J., Look, A. T. Genomic organization, chromosomal localization, and independent expression of human cyclin D genes. Genomics 13: 565-574, 1992. [PubMed: 1386335] [Full Text: https://doi.org/10.1016/0888-7543(92)90126-d]
Jeong, O.-S., Chae, Y.-C., Jung, H., Park, S. C., Cho, S.-J., Kook, H., Seo, S. Long noncoding RNA linc00598 regulates CCND2 transcription and modulates the G1 checkpoint. Sci. Rep. 6: 32172, 2016. Note: Electronic Article. [PubMed: 27572135] [Full Text: https://doi.org/10.1038/srep32172]
Kim, H. A., Pomeroy, S. L., Whoriskey, W., Pawlitzky, I., Benowitz, L. I., Sicinski, P., Stiles, C. D., Roberts, T. M. A developmentally regulated switch directs regenerative growth of Schwann cells through cyclin D1. Neuron 26: 405-416, 2000. [PubMed: 10839359] [Full Text: https://doi.org/10.1016/s0896-6273(00)81173-3]
Kozar, K., Ciemerych, M. A., Rebel, V. I., Shigematsu, H., Zagozdzon, A., Sicinska, E., Geng, Y., Yu, Q., Bhattacharya, S., Bronson, R. T., Akashi, K., Sicinski, P. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118: 477-491, 2004. [PubMed: 15315760] [Full Text: https://doi.org/10.1016/j.cell.2004.07.025]
Lossos, I. S., Czerwinski, D. K., Alizadeh, A. A., Wechser, M. A., Tibshirani, R., Botstein, D., Levy, R. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. New Eng. J. Med. 350: 1828-1837, 2004. [PubMed: 15115829] [Full Text: https://doi.org/10.1056/NEJMoa032520]
Mirzaa, G. M., Parry, D. A., Fry, A. E., Giamanco, K. A., Schwartzentruber, J., Vanstone, M., Logan, C. V., Roberts, N., Johnson, C. A., Singh, S., Kholmanskikh, S. S., Adams, C., and 22 others. De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nature Genet. 46: 510-515, 2014. [PubMed: 24705253] [Full Text: https://doi.org/10.1038/ng.2948]
Xiong, Y., Menninger, J., Beach, D., Ward, D. C. Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins. Genomics 13: 575-584, 1992. [PubMed: 1386336] [Full Text: https://doi.org/10.1016/0888-7543(92)90127-e]