Alternative titles; symbols
HGNC Approved Gene Symbol: HIVEP2
Cytogenetic location: 6q24.2 Genomic coordinates (GRCh38): 6:142,751,469-142,946,365 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q24.2 | Intellectual developmental disorder, autosomal dominant 43 | 616977 | Autosomal dominant | 3 |
The HIVEP2 gene encodes a transcription factor that binds to the NFKB site of various genes (summary by Takagi et al., 2006). Members of the ZAS family, such as ZAS2 (HIVEP2), are large proteins that contain a ZAS domain, a modular protein structure consisting of a pair of C2H2 zinc fingers with an acidic-rich region and a serine/threonine-rich sequence. These proteins bind specific DNA sequences, including the kappa-B motif (GGGACTTTCC), in the promoters and enhancer regions of several genes and viruses, including human immunodeficiency virus (HIV). ZAS genes span more than 150 kb and contain at least 10 exons, one of which is longer than 5.5 kb (summary by Allen and Wu, 2005).
Using the DNA-binding domain of HIVEP1 (194540) as probe, Nomura et al. (1991) cloned HIVEP2 from T-cell and umbilical vein endothelial cell cDNA libraries. The deduced 1,833-amino acid protein has a calculated molecular mass of 202.1 kD. Northern blot analysis detected a 9.5-kb transcript in a human T-cell line and in some tumor cell lines.
Takagi et al. (2006) found expression of the Shn2 gene in the developing mouse brain, with transiently high levels in the thalamus and amygdala, and persistent expression in the neocortex and hippocampus of postnatal mice.
Nomura et al. (1991) found that expression of HIVEP2 increased about 10-fold following mitogen or phorbol ester stimulation of the Jurkat human T-cell line. HIVEP2 bound to the HIV enhancer and other related sequences. Similar to HIVEP1, HIVEP2 showed higher affinity for the major histocompatibility enhancer than for the HIV enhancer.
Dorflinger et al. (1999) showed that rodent Mibp1 bound specifically to a TC box in the human SSTR2 (182452) promoter and could activate transcription. Mibp1 interacted with Sef2 (TCF4; 602272) to enhance transcription from the basal Sstr2 promoter in murine brain.
Jin et al. (2006) found that Shn2 entered the nucleus of mouse embryonic fibroblasts upon Bmp2 (112261) stimulation and that, in cooperation with Smad1 (601595)/Smad4 (600993) and Cebp-alpha (CEBPA; 116897), Shn2 induced the expression of Ppar-gamma-2 (PPARG; 601487), a key transcription factor for adipocyte differentiation. Shn2 directly interacted with both Smad1/Smad4 and Cebpa on the Pparg2 promoter. Jin et al. (2006) concluded that Shn2-mediated BMP signaling is critical for adipogenesis.
Using yeast 2-hybrid and coimmunoprecipitation assays, Shukla et al. (2009) showed that Clic4 (606536) and Schnurri-2 interacted in cultured mouse keratinocytes. TGF-beta (TGFB1; 190180) induced association between cytoplasmic Clic4 and Schnurri-2, leading to their translocation to the nucleus. Knockdown of Clic4 or Schnurri-2 abrogated TGF-beta-induced growth inhibition. Nuclear Clic4 associated with phosphorylated Smad2 (601366) and Smad3 (603109) and protected them from dephosphorylation by nuclear protein phosphatase-1a (PPM1A; 606108). Direct targeting of Clic4 to the nucleus following Schnurri-2 depletion revealed that Schnurri-2 was required for Clic4 nuclear translocation, but not for Clic4-mediated inhibition of DNA synthesis or growth inhibition.
In mice, Staton et al. (2011) showed that repression of T-cell antigen receptor-induced (TCR) death pathways is critical for proper interpretation of positive selecting signals in vivo, and identified Schnurri-2 as a crucial death dampener. Staton et al. (2011) showed that Schnurri-2 null double-positive thymocytes inappropriately undergo negative selection in response to positive selecting signals, thus leading to disrupted T-cell development. Schnurri-2 null double-positive thymocytes are more sensitive to TCR-induced death in vitro and die in response to positive selection interactions in vivo. However, Schnurri-2-deficient thymocytes can be positively selected when TCR-induced death is genetically ablated. Shn2 levels increase after TCR stimulation, indicating that integration of multiple TCR-MHC-peptide interactions may fine-tune the death threshold. Mechanistically, Schnurri-2 functions downstream of TCR proximal signaling components to dampen Bax (600040) activation and the mitochondrial death pathway. Staton et al. (2011) concluded that their findings uncover a critical regulator of T-cell development that controls the balance between death and differentiation.
Using Southern analysis of human/rodent somatic cell hybrid DNA with a specific HIVEP2 cDNA probe, Sudo et al. (1992) assigned the gene to chromosome 6 and further localized it to 6q23-q24 by fluorescence in situ hybridization.
Stumpf (2022) mapped the HIVEP2 gene to chromosome 6q24.2 based on an alignment of the HIVEP2 sequence (GenBank BC167801) with the genomic sequence (GRCh38).
In a 21-year-old woman, born of unrelated German patients, with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Rauch et al. (2012) identified a de novo heterozygous truncating mutation in the HIVEP2 gene (143054.0001). The authors postulated haploinsufficiency as the disease mechanism, but functional studies of the variant and studies of patient cells were not performed. The patient was initially ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing.
In 2 unrelated children with MRD43, Srivastava et al. (2016) identified de novo heterozygous truncating mutations in the HIVEP2 gene (143054.0002-143054.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were predicted to result in a loss of function and haploinsufficiency of HIVEP2; functional studies of the variants and studies of patient cells were not performed.
Steinfeld et al. (2016) identified 6 different de novo heterozygous truncating mutations in the HIVEP2 gene (see, e.g., 143054.0004-143054.0006) in 6 unrelated children with MRD43. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were predicted to result in a loss of function and haploinsufficiency of HIVEP2; functional studies of the variants and studies of patient cells were not performed.
Jin et al. (2006) found that Shn2 -/- mice were slightly smaller than wildtype mice postnatally and at 9 weeks of age. The fat mass in Shn2 -/- mice was markedly reduced compared to wildtype mice. Other tissues, including liver, heart, and kidney, had weights similar to wildtype controls, and there were no gross abnormalities. There was no significant difference in brown adipose tissue between Shn2 -/- and wildtype mice. In culture, Shn2 -/- mouse embryonic fibroblasts did not efficiently differentiate into adipocytes.
Takagi et al. (2006) found that Shn2-null mice had behavioral abnormalities, including increased anxiety and hyperactivity, compared to wildtype mice. Mutant mice showed hypersensitivity to stress, which was associated with increased plasma levels of stress-induced corticosterone.
Jones et al. (2010) stated that Shn2 -/- mice display a modest low-turnover osteopenia due to reduced osteoclast and osteoblast function, whereas Shn3 (HIVEP3; 606649) -/- mice show severe osteosclerosis due to increased osteoblast activity and elevated rate of bone formation. Jones et al. (2010) found that Shn2 -/- Shn3 -/- double-knockout mice displayed severe growth retardation resulting in dwarfism and did not survive beyond 3 weeks of age. Shn2 -/- Shn3 -/- skeletal defects were due to shortening of both axial and appendicular skeletons, incomplete formation of thoracic vertebrae, impaired sternum development, and shortening of proximal and distal limb bones. Increased bone mass in Shn2 -/- Shn3 -/- mice was similar to that observed in Shn3 -/- mice and was due to elevated osteoblast activity. Complete ablation of both Shn2 and Shn3 was necessary to perturb growth plate maturation, whereas deletion of a single Shn3 allele was sufficient to cause increased bone mass, which could be augmented by deletion of an Shn2 allele.
In a 21-year-old woman (patient BO63/11), born of unrelated German patients, with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Rauch et al. (2012) identified a de novo heterozygous 1-bp deletion (c.5737delG, NM_006734.3) in exon 9 of the HIVEP2 gene, resulting in a frameshift and premature termination (Asp1913MetfsTer15). The patient also carried a missense Q335R variant in the KDM1B gene (613081), which was of uncertain significance. The patient was initially ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing (Rauch et al., 2012) and was further studied by Srivastava et al. (2016). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 2,500 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency of HIVEP2.
In a 4-year-old girl (patient 1) with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Srivastava et al. (2016) identified a de novo heterozygous c.2827C-T transition (c.2827C-T, NM_006734.3) in exon 5 of the HIVEP2 gene, resulting in an arg943-to-ter (R943X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 2,500 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency of HIVEP2.
In a 4-year-old boy (patient 2) with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Srivastava et al. (2016) identified a de novo heterozygous c.3556C-T transition (c.3556C-T, NM_006734.3) in exon 5 of the HIVEP2 gene, resulting in a gln1186-to-ter (Q1186X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 2,500 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency of HIVEP2.
In a 7-year-old girl (patient 1) with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Steinfeld et al. (2016) identified a de novo heterozygous c.6475G-T transversion in the HIVEP2 gene, resulting in a gly2159-to-ter (G2159X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies and studies of patient cells were not performed.
In a 14-year-old girl (patient 2) with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Steinfeld et al. (2016) identified a de novo heterozygous c.2857G-T transversion in the HIVEP2 gene, resulting in a glu953-to-ter (E953X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies and studies of patient cells were not performed.
In a 10-year-old boy (patient 3) with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Steinfeld et al. (2016) identified a de novo heterozygous 1-bp duplication (c.5614dupG) in the HIVEP2 gene, resulting in a frameshift and premature termination (Glu1872GlyfsTer16). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies and studies of patient cells were not performed.
Allen, C. E., Wu, L.-C. ZAS zinc finger proteins: the other kappa-B-binding protein family. In: Iuchi, S; Kuldell, N. (eds.): Zinc Finger Proteins: From Atomic Contact to Cellular Function. Georgetown, Tex.: Landes Bioscience 2005. Pp. 213-220.
Dorflinger, U., Pscherer, A., Moser, M., Rummele, P., Schule, R., Buettner, R. Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain. Molec. Cell. Biol. 19: 3736-3747, 1999. [PubMed: 10207097] [Full Text: https://doi.org/10.1128/MCB.19.5.3736]
Jin, W., Takagi, T., Kanesashi, S., Kurahashi, T., Nomura, T., Harada, J., Ishii, S. Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins. Dev. Cell 10: 461-471, 2006. [PubMed: 16580992] [Full Text: https://doi.org/10.1016/j.devcel.2006.02.016]
Jones, D. C., Schweitzer, M. N., Wein, M., Sigrist, K., Takagi, T., Ishii, S., Glimcher, L. H. Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3. Proc. Nat. Acad. Sci. 107: 8254-8258, 2010. [PubMed: 20404140] [Full Text: https://doi.org/10.1073/pnas.1003727107]
Nomura, N., Zhao, M.-J., Nagase, T., Maekawa, T., Ishizaki, R., Tabata, S., Ishii, S. HIV-EP2, a new member of the gene family encoding the human immunodeficiency virus type 1 enhancer-binding protein: comparison with HIV-EP1/PRDII-BF1/MBP-1. J. Biol. Chem. 266: 8590-8594, 1991. [PubMed: 2022670]
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Shukla, A., Malik, M., Cataisson, C., Ho, Y., Friesen, T., Suh, K. S., Yuspa, S. H. TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3. Nature Cell Biol. 11: 777-784, 2009. [PubMed: 19448624] [Full Text: https://doi.org/10.1038/ncb1885]
Srivastava, S., Engels, H., Schanze, I., Cremer, K., Wieland, T., Menzel, M., Schubach, M., Biskup, S., Kreiss, M., Endele, S., Strom, T. M., Wieczorek, D, Zenker, M., Gupta, S., Cohen, J., Zink, A. M., Naidu, S. Loss-of-function variants in HIVEP2 are a cause of intellectual disability. Europ. J. Hum. Genet. 24: 556-561, 2016. [PubMed: 26153216] [Full Text: https://doi.org/10.1038/ejhg.2015.151]
Staton, T. L., Lazarevic, V., Jones, D. C., Lanser, A. J., Takagi, T., Ishii, S., Glimcher, L. H. Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472: 105-109, 2011. [PubMed: 21475200] [Full Text: https://doi.org/10.1038/nature09848]
Steinfeld, H., Cho, M. T., Retterer, K., Person, R., Schaefer, G. B., Danylchuk, N., Malik, S., Wechsler, S. B., Wheeler, P. G., van Gassen, K. L. I., Terhal, P. A., Verhoeven, V. J. M., van Slegtenhorst, M. A., Monaghan, K. G., Henderson, L. B., Chung, W. K. Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features. Neurogenetics 17: 159-164, 2016. [PubMed: 27003583] [Full Text: https://doi.org/10.1007/s10048-016-0479-z]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/20/2022.
Sudo, T., Ozawa, K., Soeda, E.-I., Nomura, N., Ishii, S. Mapping of the human gene for the human immunodeficiency virus type 1 enhancer binding protein HIV-EP2 to chromosome 6q23-q24. Genomics 12: 167-170, 1992. [PubMed: 1733857] [Full Text: https://doi.org/10.1016/0888-7543(92)90423-p]
Takagi, T., Jin, W., Taya, K., Watanabe, G., Mori, K., Ishii, S. Schnurri-2 mutant mice are hypersensitive to stress and hyperactive. Brain Res. 1108: 88-97, 2006. [PubMed: 16836985] [Full Text: https://doi.org/10.1016/j.brainres.2006.06.018]