Alternative titles; symbols
HGNC Approved Gene Symbol: ASXL1
SNOMEDCT: 720565000;
Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38): 20:32,358,331-32,439,319 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.21 | Bohring-Opitz syndrome | 605039 | Autosomal dominant | 3 |
| Myelodysplastic syndrome, somatic | 614286 | 3 |
ASXL1 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 required to maintain both activation and silencing of homeotic loci (summary by Fisher et al., 2003).
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1999) obtained a partial ASXL1 clone, which they designated KIAA0978. RT-PCR ELISA detected low to moderate expression in all adult and fetal tissues and specific adult brain regions examined.
By searching EST databases for sequences similar to Drosophila asx and by screening an adult heart cDNA library, Fisher et al. (2003) obtained overlapping clones covering the ASXL1 coding sequence. The deduced 1,541-amino acid protein has a calculated molecular mass of 165.5 kD. The N-terminal region of ASXL1 contains a serine-rich region, 3 nuclear localization signals, a PEST motif, a nuclear receptor-binding motif, and a region that shares high sequence identity with Drosophila asx, which Fisher et al. (2003) called the asx homology domain (AHD). The AHD is followed by a glycine-rich region, 3 additional PEST sequences, and a C-terminal plant homeodomain (PHD). ASXL1 lacks the AT-hook motif and the nucleotide-binding motif of Drosophila asx. ASXL1 shares over 70% amino acid identity with mouse Asxl1 and 21% identity with Drosophila asx. Northern blot analysis detected variable expression of ASXL1 transcripts of 8.0 and 6.0 kb. Expression was highest in testis, moderate in thymus, ovary, lymph node, and appendix, very low in other tissues, and undetectable in adult liver and kidney. The 8.0-kb transcript was dominant in most tissues, but the 6.0-kb transcript was dominant in testis. Testis also expressed a 5.0-kb transcript that was not detected in other tissues.
Fisher et al. (2003) determined that the ASXL1 gene contains 13 exons and spans 81 kb. Exon 13 contains the entire 3-prime UTR and is almost 5 kb long. The smallest exon, exon 3, is 3 bp long.
Using FISH and genomic sequence analysis, Fisher et al. (2003) mapped the ASXL1 gene to chromosome 20q11.21, between the KIF3B gene (603754) and the DNMT3B gene (602900).
Using mouse and human cell lines, Park et al. (2011) showed that mouse Asxl1 and human ASXL2 (612991) 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.
Somatic Mutations in Myeloid Malignancies
Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene may act as a tumor suppressor in myeloid malignancies. They identified heterozygous somatic mutations in the ASXL1 gene in 5 (16%) of 38 myelodysplastic syndrome (MDS; 614286)/acute myeloid leukemia (AML; 601626) samples. Somatic ASXL1 mutations were also found in 19 (43%) of 44 chronic myelomonocytic leukemia (CMML; see 607785) samples. All the mutations were in exon 12 and resulted in truncation of the C terminus PHD finger of the protein. The findings suggested that regulators of gene expression via DNA methylation, histone modification, and chromatin remodeling could be altered in myelodysplastic syndromes and some leukemias. The same group (Carbuccia et al., 2009) identified heterozygous somatic truncating ASXL1 mutations in 5 (7.8%) of 64 myeloproliferative neoplasms, including 1 essential thrombocythemia (187950), 3 primary myelofibrosis (254450), and 1 AML.
Chou et al. (2010) identified somatic mutations in exon 12 of the ASXL1 gene disrupting the PHD domain in 54 (10.8%) of 501 adults with de novo AML. There was a similar frequency of ASXL1 mutations in those with a normal karyotype (8.9%) and those with abnormal cytogenetics (12.9%), but 39 of the 54 patients with ASXL1 mutations had concurrent mutations in other genes. ASXL1 mutations were closely associated with older age, male sex, isolated trisomy 8, RUNX1 (151385) mutations, and expression of HLA-DR and CD34, but inversely associated with t(15;17), complex cytogenetics, FLT3-internal tandem duplication, NPM1 (164040) mutations, WT1 (607102) mutations, and expression of CD33 (159590) and CD15. Patients with ASXL1 mutations had a shorter overall survival than patients without mutations, but mutation status was not an independent adverse prognostic factor in multivariate analysis. Sequential analyses of patient samples showed that the original ASXL1 mutations were lost at relapse and/or refractory status in 2 of the 6 relapsed ASXL1-mutated patients studied, whereas 2 of the 109 ASXL1-wildtype patients acquired a novel ASXL1 mutation at relapse. Chou et al. (2010) suggested that AML with ASXL1 mutations showed distinct clinical and biologic features and that ASXL1 mutation status can change during disease evolution.
Bohring-Opitz Syndrome
By exome sequencing in combination with direct sequencing, Hoischen et al. (2011) identified 7 different de novo heterozygous nonsense or truncating mutations in the ASXL1 gene (see, e.g., 612990.0001-612990.0005) in 7 of 13 unrelated patients with Bohring-Opitz syndrome (605039), a severe developmental and malformation disorder characterized by intrauterine growth retardation, poor feeding, profound mental retardation, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints. Hoischen et al. (2011) postulated a loss-of-function mechanism. The ASXL1 gene is involved in the maintenance of both activation and silencing of the HOX genes, which are involved in body patterning, as well as in chromatin remodeling, although the patients did not have any specific homeotic transformations.
In 2 unrelated patients with classic features of Bohring-Opitz syndrome, Magini et al. (2012) identified 2 different de novo heterozygous truncating mutations in the ASXL1 gene (612990.0006 and 612990.0007).
In a patient with a mild case of Bohring-Opitz syndrome, Leon et al. (2020) identified heterozygosity for a de novo splicing mutation in the ASXL1 gene (612990.0008).
Abdel-Wahab et al. (2013) found that Asxl1-null mice had multiple developmental abnormalities, including anophthalmia, microcephaly, cleft palate, and mandibular malformation. Hemopoietic-specific deletion of Asxl1 in mice resulted in progressive, multilineage cytopenias and dysplasia with increased numbers of hemopoietic stem/progenitor cells, characteristic of human MDS. Serial transplantation of Asxl1-null hemopoietic cells caused a lethal myeloid disorder with a shorter latency than primary Asxl1-null mice. Deletion of Asxl1 reduced hemopoietic stem cell self-renewal, which was restored by concurrent deletion of Tet2 (612839), a gene frequently co-mutated with ASXL1 in MDS patients. Asxl1/Tet2 double-knockout mice had an MDS phenotype with more rapid mortality compared with single gene-knockout mice. Asxl1 loss resulted in a genomewide reduction of histone H3 lys27 trimethylation and dysregulated expression of known regulators of hemopoiesis. Chromosome immunoprecipitation of Asxl1 followed by DNA sequencing in mouse hemopoietic cells identified a subset of genes differentially regulated by Asxl1. Abdel-Wahab et al. (2013) concluded that ASXL1 is important in development and hemopoiesis.
In a patient with Bohring-Opitz syndrome (605039), Hoischen et al. (2011) identified a de novo heterozygous 2773C-T transition in the ASXL1 gene, resulting in a gln925-to-ter (Q925X) substitution. The patient died at age 6 years.
In a 7-year-old girl with Bohring-Opitz syndrome (605039), Hoischen et al. (2011) identified a de novo heterozygous 1210C-T transition in the ASXL1 gene, resulting in an arg404-to-ter (R404X) substitution.
In a 2.5-year-old girl with Bohring-Opitz syndrome (605039), Hoischen et al. (2011) identified a de novo heterozygous 3083C-A transversion in the ASXL1 gene, resulting in a ser1028-to-ter (S1028X) substitution.
In a 24-year-old woman with Bohring-Opitz syndrome (605039), Hoischen et al. (2011) identified a de novo heterozygous 1-bp duplication at nucleotide 2535 in the ASXL1 gene, resulting in a frameshift and premature termination (Ser846GlnfsTer5).
In a female infant with Bohring-Opitz syndrome (605039), Hoischen et al. (2011) identified a de novo heterozygous 2197C-T transition in the ASXL1 gene, resulting in a gln733-to-ter (Q733X) substitution. The patient died 23 hours after birth.
In a 3-year-old girl with typical features of Bohring-Opitz syndrome (605039), Magini et al. (2012) identified a de novo heterozygous 5-bp deletion in the ASLX1 gene (2407_2411del), resulting in a frameshift and premature termination (Gln803ThrfsTer17). The mutation was not found in 2 large databases.
In a 7-year-old boy with typical features of Bohring-Opitz syndrome (605039), Magini et al. (2012) identified a de novo heterozygous 2893C-T transition in the ASLX1 gene, resulting in an arg965-to-ter (R965X) substitution. The mutation was not found in 2 large databases.
By whole-exome sequencing in a 5-year-old girl with a mild case of Bohring-Opitz syndrome (BOPS; 605039), Leon et al. (2020) identified a de novo heterozygous c.1720A-G transition (ENST00000375687) in the ASLX1 gene at the canonical splice acceptor site of intron 12, resulting in a frameshift and a premature stop codon after 21 residues (Ile574ValfsTer22). Analysis of the mRNA splicing pattern on patient fibroblasts by Sanger sequencing showed that the mutation leads to full retention of intron 12. The resulting protein is predicted to lack the C terminus end of the protein. The patient had previously been reported by Yuan et al. (2019) as patient 3 with a Cornelia de Lange-like phenotype.
Abdel-Wahab, O., Gao, J., Adli, M., Dey, A., Trimarchi, T., Chung, Y. R., Kuscu, C., Hricik, T., Ndiaye-Lobry, D., LaFave, L. M., Koche, R., Shih, A. H., and 15 others. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J. Exp. Med. 210: 2641-2659, 2013. [PubMed: 24218140] [Full Text: https://doi.org/10.1084/jem.20131141]
Carbuccia, N., Murati, A., Trouplin, V., Brecqueville, M., Adelaide, J., Rey, J., Vainchenker, W., Bernard, O. A., Chaffanet, M., Vey, N., Birnbaum, D., Mozziconacci, M. J. Mutations of ASXL1 gene in myeloproliferative neoplasms. (Letter) Leukemia 23: 2183-2186, 2009. [PubMed: 19609284] [Full Text: https://doi.org/10.1038/leu.2009.141]
Chou, W.-C., Huang, H.-H., Hou, H.-A., Chen, C.-Y., Tang, J.-L., Yao, M., Tsay, W., Ko, B.-S., Wu, S.-J., Huang, S.-Y., Hsu, S.-C., Chen, Y.-C., Huang, Y.-N., Chang, Y.-C., Lee, F.-Y., Liu, M.-C., Liu, C.-W., Tseng, M.-H., Huang, C.-F., Tien, H.-F. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood 116: 4086-4094, 2010. [PubMed: 20693432] [Full Text: https://doi.org/10.1182/blood-2010-05-283291]
Fisher, C. L., Berger, J., Randazzo, F., Brock, H. W. A human homolog of Additional sex combs, ADDITIONAL SEX COMBS-LIKE 1, maps to chromosome 20q11. Gene 306: 115-126, 2003. [PubMed: 12657473] [Full Text: https://doi.org/10.1016/s0378-1119(03)00430-x]
Gelsi-Boyer, V., Trouplin, V., Adelaide, J., Bonansea, J., Cervera, N., Carbuccia, N., Lagarde, A., Prebet, T., Nezri, M., Sainty, D., Olschwang, S., Xerri, L., Chaffanet, M., Mozziconacci, M.-J., Vey, N., Birnbaum, D. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Brit. J. Haemat. 145: 788-800, 2009. [PubMed: 19388938] [Full Text: https://doi.org/10.1111/j.1365-2141.2009.07697.x]
Hoischen, A., van Bon, B. W. M., Rodriguez-Santiago, B., Gilissen, C., Vissers, L. E. L. M., de Vries, P., Janssen, I., van Lier, B., Hastings, R., Smithson, S. F., Newbury-Ecob, R., Kjaergaard, S., and 11 others. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nature Genet. 43: 729-731, 2011. [PubMed: 21706002] [Full Text: https://doi.org/10.1038/ng.868]
Leon, E., Diaz, J., Castilla-Vallmanya, L., Grinberg, D., Balcells, S., Urreizti, R. Extending the phenotypic spectrum of Bohring-Opitz syndrome: mild case confirmed by functional studies. Am. J. Med. Genet. 182A: 201-204, 2020. [PubMed: 31692235] [Full Text: https://doi.org/10.1002/ajmg.a.61397]
Magini, P., Della Monica, M., Uzielli, M. L. G., Mongelli, P., Scarselli, G., Gambineri, E., Scarano, G., Seri, M. Two novel patients with Bohring-Opitz syndrome caused by de novo ASXL1 mutations. Am. J. Med. Genet. 158A: 917-921, 2012. [PubMed: 22419483] [Full Text: https://doi.org/10.1002/ajmg.a.35265]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 63-70, 1999. [PubMed: 10231032] [Full Text: https://doi.org/10.1093/dnares/6.1.63]
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]
Yuan, B., Neira, J., Pehlivan, D., Santiago-Sim, T., Song, X., Rosenfeld, J., Posey, J. E., Patel, V., Jin, W., Adam, M. P., Baple, E. L., Dean, J., and 34 others. Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. Genet. Med. 21: 663-675, 2019. [PubMed: 30158690] [Full Text: https://doi.org/10.1038/s41436-018-0085-6]