Alternative titles; symbols
HGNC Approved Gene Symbol: CNOT2
Cytogenetic location: 12q15 Genomic coordinates (GRCh38): 12:70,243,018-70,354,993 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q15 | Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies | 618608 | Autosomal dominant | 3 |
The yeast CCR4-NOT protein complex is a global regulator of RNA polymerase II transcription. It is comprised, in part, of CCR4 (see 608951), NOT1 to NOT5, and CAF1 (also referred to as POP2). By searching sequence databases, Albert et al. (2000) identified human ESTs encoding homologs of yeast NOT1, NOT2, NOT3, NOT4, and CAF1. They assembled a human NOT2 cDNA containing a full-length coding sequence. The deduced 540-amino acid human NOT2 protein shares 26% overall sequence identity with the 191-amino acid yeast NOT2 protein. Compared to yeast NOT2, human NOT2 has an N-terminal extension. Human NOT2 contains an N-terminal putative bipartite nuclear localization signal. Using the yeast 2-hybrid assay, Albert et al. (2000) demonstrated that recombinant human NOT2 can interact with yeast NOT1 and an N-terminally truncated human NOT1 protein (604917); it did not significantly interact with human NOT3 (604910) or yeast CCR4. Northern blot analysis detected a 3.2-kb NOT2 transcript in all human tissues examined, namely brain, heart, lung, liver, kidney, small intestine, colon, spleen, thymus, peripheral blood leukocytes, skeletal muscle, and placenta. Like the expression of human NOT1, NOT3, and CALIF (603731), NOT2 expression was high in brain, kidney, and placenta and very low in skeletal muscle and colon. Albert et al. (2000) found that recombinant human NOT2 could not complement the temperature-sensitive phenotype conferred by the yeast not2-1 mutation.
Uehara et al. (2019) stated that the CNOT2 gene contains 21 exons.
Alesi et al. (2017) stated that the CNOT2 gene maps to chromosome 15q15.
Sessions et al. (2009) identified insect host factors required for dengue virus (see 614371) propagation by carrying out a genomewide RNA interference screen in D. melanogaster cells using a well established 22,632 double-stranded RNA library. This screen identified 116 candidate dengue virus host factors (DVHFs). Although some were previously associated with flaviviruses, most of the DVHFs were newly implicated in dengue virus propagation. The dipteran DVHFs had 82 readily recognizable human homologs and, using a targeted short interfering RNA screen, they showed that 42 of these are human DVHFs. These include NPR2 (108961), SEC61B (609214), TMEM214, TAZ (300394), EXDL2, and CNOT2. Sessions et al. (2009) concluded that this overlap indicates notable conservation of required factors between dipteran and human hosts.
In a 13-year-old boy with intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (IDNADFS; 618608), Alesi et al. (2019) identified a de novo heterozygous 85-kb intragenic deletion within the CNOT2 gene (604909.0001). The deletion was found by chromosomal microarray analysis. Examination of the ExAC database indicated that loss-of-function variants in the CNOT2 gene are not tolerated. Although functional studies of the variant and studies of patient cells were not performed, Alesi et al. (2019) suggested that haploinsufficiency for CNOT2 is responsible for the phenotype.
In a 6-year-old Japanese boy with IDNADFS, Uehara et al. (2019) identified a de novo heterozygous nonsense mutation in the CNOT2 gene (K316X; 604909.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 2,048 control Japanese individuals. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.
In a 13-year-old boy with intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (IDNADFS; 618608), Alesi et al. (2019) identified a de novo heterozygous 85-kb intragenic deletion (chr12.70,672,317-70,757,341, GRCh37) involving exons 3 to exon 15 within the CNOT2 gene. The deletion was found by chromosomal microarray analysis. Examination of the ExAC database indicated that loss-of-function variants in the CNOT2 gene are not tolerated. Although functional studies of the variant and studies of patient cells were not performed, Alesi et al. (2019) suggested that haploinsufficiency for CNOT2 is responsible for the phenotype.
In a 6-year-old Japanese boy with intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (IDNADFS; 618608), Uehara et al. (2019) identified a de novo heterozygous c.946A-T transversion (c.946A-T, NM_001199302.1) in exon 11 of the CNOT2 gene, resulting in a lys316-to-ter (K316X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 2,048 control Japanese individuals. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.
Albert, T. K., Lemaire, M., van Berkum, N. L., Gentz, R., Collart, M. A., Timmers, H. T. M. Isolation and characterization of human orthologs of yeast CCR4-NOT complex subunits. Nucleic Acids Res. 28: 809-817, 2000. [PubMed: 10637334] [Full Text: https://doi.org/10.1093/nar/28.3.809]
Alesi, V., Loddo, S., Cali, F., Orlando, V., Genovese, S., Ferretti, D., Calacci, C., Calvieri, G., Falasca, R., Ulgheri, L., Drago, F., Dallapiccola, B., Baban, A., Novelli, A. A heterozygous, intragenic deletion of CNOT2 recapitulates the phenotype of 12q15 deletion syndrome. Am. J. Med. Genet. 179A: 1615-1621, 2019. [PubMed: 31145527] [Full Text: https://doi.org/10.1002/ajmg.a.61217]
Alesi, V., Loddo, S., Grispo, M., Riccio, S., Montella, A. C., Dallapiccola, B., Ulgheri, L., Novelli, A. Reassessment of the 12q15 deletion syndrome critical region. Europ. J. Med. Genet. 60: 220-223, 2017. [PubMed: 28159701] [Full Text: https://doi.org/10.1016/j.ejmg.2017.01.009]
Sessions, O. M., Barrows, N. J., Souza-Neto, J. A., Robinson, T. J., Hershey, C. L., Rodgers, M. A., Ramirez, J. L., Dimopoulos, G., Yang, P. L., Pearson, J. L., Garcia-Blanco, M. A. Discovery of insect and human dengue virus host factors. Nature 458: 1047-1050, 2009. [PubMed: 19396146] [Full Text: https://doi.org/10.1038/nature07967]
Uehara, T., Tsuchihashi, T., Yamada, M., Suzuki, H., Takenouchi, T., Kosaki, K. CNOT2 haploinsufficiency causes a neurodevelopmental disorder with characteristic facial features. Am. J. Med. Genet. 179: 2506-2509, 2019. [PubMed: 31512373] [Full Text: https://doi.org/10.1002/ajmg.a.61356]