Alternative titles; symbols
HGNC Approved Gene Symbol: ASXL2
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38) : 2:25,733,753-25,878,487 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | Shashi-Pena syndrome | 617190 | Autosomal dominant | 3 |
ASXL2 is a human homolog of the Drosophila asx gene. Drosophila asx is an enhancer of trithorax (see 159555) and polycomb (see 610231) (ETP) gene that encodes a chromatin protein with dual functions in transcriptional activation and silencing (summary by Katoh and Katoh, 2003).
By sequencing clones obtained from a size-fractionated human hippocampus cDNA library, Nagase et al. (2000) obtained a partial ASXL2 clone, which they designated KIAA1685. RT-PCR ELISA detected relatively low expression in all adult and fetal tissues and specific adult brain regions examined.
By searching databases for sequences similar to ASXL1 (612990), followed by EST database analysis, Katoh and Katoh (2003) obtained a full-length ASXL2 cDNA. The deduced 1,435-amino acid protein shares 29.8% identity with ASXL1. ASXL1 and ASXL2 share significant homology in their N-terminal and middle domains, which the authors designated the ASXN and ASXM domains, respectively, and both proteins have a C-terminal plant homeodomain (PHD). Katoh and Katoh (2003) also identified a putative splice variant of mouse Asxl2, which encodes a protein with an in-frame internal deletion of about 50 amino acids compared with full-length human ASXL2.
Ramocki et al. (2003) stated that in situ hybridization of mouse Asxl2 demonstrated ubiquitous expression in the central nervous system from embryonic day 9.5 to 15.5.
Katoh and Katoh (2003) determined that the ASXL2 gene contains 13 coding exons that span about 139 kb.
Using mouse and human cell lines, Park et al. (2011) showed that mouse Asxl1 and human ASXL2 interacted with PPAR-alpha (PPARA; 170998) and PPAR-gamma (PPARG; 601487) and played opposite roles in adipogenesis. Asxl1 suppressed transactivation activity of ligand-bound PPAR-gamma and blocked adipogenic differentiation in mouse 3T3-L1 cells, whereas ASXL2 promoted these activities. Mutation analysis revealed that the heterochromatin protein-1 (HP1; see 604478)-binding domain of Asxl1 was required for its repressive activity. Without the HP1-binding domain, Asxl1 behaved like ASXL2 to promote PPAR-gamma activity and induce adipogenesis. In chromatin immunoprecipitation assays in 3T3-L1 cells, Asxl1 occupied the promoter of the endogenous PPAR-gamma target Ap2 (FABP4; 600434) together with the inhibitory factors HP1-alpha (CBX5; 604478) and lys9-methylated histone H3 (see 602810), whereas ASXL2 occupied the Ap2 promoter together with the activating factors histone lysine N-methyltransferase MLL1 (159555) and lys9-acetylated and lys4-methylated H3 histones. Microarray analysis showed that Asxl1 repressed, whereas ASXL2 increased, the expression of a subset of adipogenic genes, most of which are PPAR-gamma targets. Park et al. (2011) concluded that ASXL1 is a PPAR-gamma corepressor and that ASXK2 is a PPAR-gamma coactivator. They proposed that ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPAR-gamma.
By genomic sequence analysis, Katoh and Katoh (2003) mapped the ASXL2 gene to chromosome 2p23.3, where it lies between the DNMT3A (602769) and KIF3C (602845) genes. This region of chromosome 2p is paralogous with the DNMT3B (602900)-ASXL1-KIF3B (603754) locus on chromosome 20q.
In 6 unrelated patients with Shashi-Pena syndrome (SHAPNS; 617190), Shashi et al. (2016) identified 6 different de novo heterozygous truncating mutations in the ASXL2 gene (612991.0001-612991.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Analysis of cells from 3 patients showed that the mutant transcripts were expressed and not subject to nonsense-mediated mRNA decay, providing support for a dominant-negative effect rather than haploinsufficiency. Additional functional studies were not performed. The patients were ascertained from several large cohorts of patients with neurodevelopmental disorders including a total of 12,030 individuals: statistical analysis indicated that the probability of these 6 de novo truncating mutations occurring by chance in this group was small (1.47 x 10(-10)). Examination of the ExAC browser identified 6 different heterozygous putative loss-of-function ASXL2 variants, which is fewer than expected and suggests that ASXL2 is highly intolerant of such variants.
Baskind et al. (2009) found that Asxl2-null mice had reduced body weight, skeletal and vertebral abnormalities, and cardiac dysfunction with congenital heart malformations, enlarged hearts, and premature death. Asxl2 was also ubiquitously expressed in the brain of mouse embryos.
Izawa et al. (2015) found that Asxl2 in mice regulates skeletal, lipid, and glucose homeostasis. Asxl2-null mice developed osteopetrosis, insulin resistance, glucose intolerance, and lipodystrophy. Cellular studies showed that Asxl2 interacted with Pparg (601487) and Rank (603499) to regulate downstream signaling pathways.
In a patient (patient 1) with Shashi-Pena syndrome (SHAPNS; 617190), Shashi et al. (2016) identified a de novo heterozygous 1-bp deletion (c.2424delC, NM_018263.4) in the last exon (exon 12) of the ASXL2 gene, resulting in a frameshift and premature termination (Thr809ProfsTer32). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, and ExAC databases. Analysis of patient cells showed that the mutant transcript was expressed and not subject to nonsense-mediated mRNA decay, providing support for a dominant-negative effect rather than haploinsufficiency. Additional functional studies were not performed.
In a patient (patient 2) with Shashi-Pena syndrome (SHAPNS; 617190), Shashi et al. (2016) identified a de novo heterozygous 1-bp duplication (c.2081dupG, NM_018263.4) in the last exon (exon 12) of the ASXL2 gene, resulting in a frameshift and premature termination (Gly696ArgfsTer11). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, and ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In a patient (patient 3) with Shashi-Pena syndrome (SHAPNS; 617190), Shashi et al. (2016) identified a de novo heterozygous 4-bp deletion (c.1225_1228delCCAA, NM_018263.4) in the second to last exon (exon 10) of the ASXL2 gene, resulting in a frameshift and premature termination (Pro409AsnfsTer13). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, and ExAC databases. Analysis of patient cells showed that the mutant transcript was expressed and not subject to nonsense-mediated mRNA decay, providing support for a dominant-negative effect rather than haploinsufficiency. Additional functional studies were not performed.
In a patient (patient 4) with Shashi-Pena syndrome (SHAPNS; 617190), Shashi et al. (2016) identified a de novo heterozygous 1-bp deletion (c.2472delC, NM_018263.4) in the last exon (exon 12) of the ASXL2 gene, resulting in a frameshift and premature termination (Ser825ValfsTer16). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, and ExAC databases. Analysis of patient cells showed that the mutant transcript was expressed and not subject to nonsense-mediated mRNA decay, providing support for a dominant-negative effect rather than haploinsufficiency. Additional functional studies were not performed.
In a patient (patient 5) with Shashi-Pena syndrome (SHAPNS; 617190), Shashi et al. (2016) identified a de novo heterozygous 4-bp deletion (c.2971_2974delGGAG, NM_018263.4) in the last exon (exon 12) of the ASXL2 gene, resulting in a frameshift and premature termination (Gly991ArgfsTer3). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, and ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In a patient (patient 6) with Shashi-Pena syndrome (SHAPNS; 617190), Shashi et al. (2016) identified a de novo heterozygous c.1288G-T transversion (c.1288G-T, NM_018263.4) in the second to last exon (exon 10) of the ASXL2 gene, resulting in glu430-to-ter (E430X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, and ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
Baskind, H. A., Na, L., Ma, Q., Patel, M. P., Geenen, D. L., Wang, Q. T. Functional conservation of Asxl2, a murine homolog for the Drosophila enhancer of trithorax and polycomb group gene Asx. PLoS One 4: e4750, 2009. Note: Electronic Article. [PubMed: 19270745] [Full Text: https://doi.org/10.1371/journal.pone.0004750]
Izawa, T., Rohatgi, N., Fukunaga, T., Wang, Q.-T., Silva, M. J., Gardner, M. J., McDaniel, M. L., Abumrad, N. A., Semenkovich, C. F., Teitelbaum, S. L., Zou, W. ASXL2 regulates glucose, lipid, and skeletal homeostasis. Cell Rep. 11: 1625-1637, 2015. [PubMed: 26051940] [Full Text: https://doi.org/10.1016/j.celrep.2015.05.019]
Katoh, M., Katoh, M. Identification and characterization of ASXL2 gene in silico. Int. J. Oncol. 23: 845-850, 2003. [PubMed: 12888926]
Nagase, T., Kikuno, R., Hattori, A., Kondo, Y., Okumura, K., Ohara, O. Prediction of the coding sequences of unidentified human genes, XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 347-355, 2000. [PubMed: 11214970] [Full Text: https://doi.org/10.1093/dnares/7.6.347]
Park, U.-H., Yoon, S. K., Park, T., Kim, E.-J., Um, S.-J. Additional sex comb-like (ASXL) proteins 1 and 2 play opposite roles in adipogenesis via reciprocal regulation of peroxisome proliferator-activated receptor gamma. J. Biol. Chem. 286: 1354-1363, 2011. [PubMed: 21047783] [Full Text: https://doi.org/10.1074/jbc.M110.177816]
Ramocki, M. B., Dowling, J., Grinberg, I., Kimonis, V. E., Cardoso, C., Gross, A., Chung, J., Martin, C. L., Ledbetter, D. H., Dobyns, W. B., Millen, K. J. Reciprocal fusion transcripts of two novel Zn-finger genes in a female with absence of the corpus callosum, ocular colobomas and a balanced translocation between chromosomes 2p24 and 9q32. Europ. J. Hum. Genet. 11: 527-534, 2003. [PubMed: 12825074] [Full Text: https://doi.org/10.1038/sj.ejhg.5200995]
Shashi, V., Pena, L. D. M., Kim, K., Burton, B., Hempel, M., Schoch, K., Walkiewicz, M., McLaughlin, H. M., Cho, M., Stong, N., Hickey, S. E., Shuss, C. M., and 23 others. De novo truncating variants in ASXL2 are associated with a unique and recognizable clinical phenotype. Am. J. Hum. Genet. 99: 991-999, 2016. Note: Erratum: Am. J. Hum. Genet. 100: 179 only, 2017. [PubMed: 27693232] [Full Text: https://doi.org/10.1016/j.ajhg.2016.08.017]