Alternative titles; symbols
HGNC Approved Gene Symbol: ESS2
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38) : 22:19,130,279-19,144,651 (from NCBI)
A group of developmental disorders, sometimes given the acronym of CATCH22 and including DiGeorge syndrome (DGS; 188400), velocardiofacial syndrome (VCFS; 192430), conotruncal anomaly face syndrome (CTAFS), and some familial or sporadic conotruncal cardiac defects (217095), has been associated with microdeletion of 22q11.2. Gong et al. (1997) noted that the proximal and distal boundaries of the smallest region of deletion overlap (SRDO, approximately 300 to 400 kb) had been defined based on breakpoint mapping data from patients with DGS/VCFS. This region was narrowed to 250 kb (minimal DGS critical region, or MDGCR) by analysis of an unbalanced 15;22 translocation in a VCFS patient. Genes that have been identified within the MDGCR include DGCR2 (600594), the citrate transport protein gene (190315), the clathrin heavy chain-like gene (601273), and DGCR5. Gong et al. (1996) identified several novel transcription units within the MDGCR, including a gene they designated DGSI.
By screening for expressed sequences in the SRDO, Lindsay et al. (1996) identified 6 distinct transcripts that were expressed in heart, including DGCR2, TUPLE1 (600237), and ES2, which is identical to DGSI.
By screening a human heart cDNA library and a mouse genomic library, Rizzu et al. (1996) obtained cDNAs encoding mouse and human ES2. Sequence analysis predicted that human ES2 is a 476-amino acid protein. Northern blot analysis detected a major 2-kb ES2 transcript in heart, brain, and skeletal muscle, with lower expression in placenta.
Gong et al. (1997) isolated cDNAs encoding human and mouse DGSI. Comparison of their predicted amino acid sequences indicated that DGSI is highly conserved. The predicted mouse protein contains 479 amino acids with 93.2% identity to the human DGSI gene.
Lindsay et al. (1998) determined that the 480-amino acid mouse Es2 protein is 93% identical to the human protein and contains a coiled-coil motif. They also identified 2 splice variants of Es2. Fluorescence microscopy demonstrated a nuclear localization. In situ hybridization analysis showed embryonic Es2 expression that was highest in the pons, with lower levels in brain, spinal cord, developing face, kidney cortex, and thymus.
Gong et al. (1997) determined that the DGSI gene contains 9 exons and spans 11 kb of genomic DNA.
Gong et al. (1996) identified the DGSI gene within the MDGCR on chromosome 22q11.2.
Rizzu et al. (1996) mapped the mouse Es2 gene to chromosome 16B1-B3. Gong et al. (1997) noted that this region of mouse chromosome 16 shares conserved linkage to the human MDGCR.
By mutation analysis in 16 patients who had no detectable 22q11.2 deletion but some of the characteristic clinical features of DGS/VCFS, Gong et al. (1997) identified 8 sequence variants in the DGSI gene. These occurred in the 5-prime untranslated region, the coding region, and the intronic regions adjacent to the intron-exon boundaries of the gene. Seven of the 8 variants were also present in normal control or unaffected family members, suggesting that they may not be of etiologic significance. Gong et al. (1997) concluded, however, that DGSI remains a candidate gene for the DGS/VCFS syndrome and related abnormalities.
By deleting a portion of mouse chromosome 16B that is homologous to human 22q11, Lindsay et al. (1999) created an animal model for DiGeorge syndrome. The region deleted extended from the Es2 gene to the Ufd1l gene (601754). The results indicated that the Es2 gene is essential for embryonic development in mice and that heterozygous deletion of this gene is not sufficient to generate cardiovascular abnormalities.
Funato et al. (2010) found that Gscl (601845) -/- mice lacked expression of Dgcr14, which is located 2 kb downstream of Gscl in the same transcriptional direction, specifically in the interpeduncular nucleus. These mice had apparently normal neural architecture, with normal distribution of neurotransmitter immunoreactivity and normal afferent and efferent connections to and from the interpeduncular nucleus. However, Gscl -/- mice showed abnormalities in rapid eye movement (REM) sleep, including reduced total time in REM sleep, fewer REM sleep episodes, reduced theta power during REM sleep, and increased arousability during REM sleep. Funato et al. (2010) concluded that the absence of Gscl and Dgcr14 in the interpeduncular nucleus results in altered regulation of REM sleep.
Funato, H., Sato, M., Sinton, C. M., Gautron, L., Williams, S. C., Skach, A., Elmquist, J. K., Skoultchi, A. I., Yanagisawa, M. Loss of Goosecoid-like and DiGeorge syndrome critical region 14 in interpeduncular nucleus results in altered regulation of rapid eye movement sleep. Proc. Nat. Acad. Sci. 107: 18155-18160, 2010. [PubMed: 20921407] [Full Text: https://doi.org/10.1073/pnas.1012764107]
Gong, W., Emanuel, B. S., Collins, J., Kim, D. H., Wang, Z., Chen, F., Zhang, G., Roe, B., Budarf, M. L. A transcription map of the DiGeorge and velo-cardio-facial syndrome minimal critical region on 22q11. Hum. Molec. Genet. 5: 789-800, 1996. [PubMed: 8776594] [Full Text: https://doi.org/10.1093/hmg/5.6.789]
Gong, W., Emanuel, B. S., Galili, N., Kim, D. H., Roe, B., Driscoll, D. A., Budarf, M. L. Structural and mutational analysis of a conserved gene (DGSI) from the minimal DiGeorge syndrome critical region. Hum. Molec. Genet. 6: 267-276, 1997. [PubMed: 9063747] [Full Text: https://doi.org/10.1093/hmg/6.2.267]
Lindsay, E. A., Botta, A., Jurecic, V., Carattini-Rivera, S., Cheah, Y.-C., Rosenblatt, H. M., Bradley, A., Baldini, A. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401: 379-383, 1999. [PubMed: 10517636] [Full Text: https://doi.org/10.1038/43900]
Lindsay, E. A., Harvey, E. L., Scambler, P. J., Baldini, A. ES2, a gene deleted in DiGeorge syndrome, encodes a nuclear protein and is expressed during early mouse development, where it shares an expression domain with a Goosecoid-like gene. Hum. Molec. Genet. 7: 629-635, 1998. [PubMed: 9499415] [Full Text: https://doi.org/10.1093/hmg/7.4.629]
Lindsay, E. A., Rizzu, P., Antonacci, R., Jurecic, V., Delmas-Mata, J., Lee, C.-C., Kim, U.-J., Scambler, P. J., Baldini, A. A transcription map in the CATCH22 critical region: identification, mapping, and ordering of four novel transcripts expressed in heart. Genomics 32: 104-112, 1996. [PubMed: 8786095] [Full Text: https://doi.org/10.1006/geno.1996.0082]
Rizzu, P., Lindsay, E. A., Taylor, C., O'Donnell, H., Levy, A., Scambler, P., Baldini, A. Cloning and comparative mapping of a gene from the commonly deleted region of DiGeorge and velocardiofacial syndromes conserved in C. elegans. Mammalian Genome 7: 639-643, 1996. [PubMed: 8703114] [Full Text: https://doi.org/10.1007/s003359900197]