Alternative titles; symbols
HGNC Approved Gene Symbol: ASXL3
SNOMEDCT: 773400009;
Cytogenetic location: 18q12.1 Genomic coordinates (GRCh38): 18:33,578,219-33,751,195 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.1 | Bainbridge-Ropers syndrome | 615485 | Autosomal dominant | 3 |
Drosophila Asx is a polycomb group protein involved in larval patterning and development. ASXL3 belongs to a group of vertebrate Asx-like proteins predicted to function as transcriptional regulators (Katoh and Katoh, 2004).
By sequencing clones from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) obtained a partial ASXL3 clone, which they designated KIAA1713. RT-PCR ELISA detected moderate ASXL3 expression in adult ovary and adult and fetal brain. Lower expression was detected in adult kidney and testis, followed by adult liver and pancreas. Little to no expression was detected in other whole tissues examined. Low to moderate ASXL3 expression was detected in all specific adult brain regions examined and spinal cord.
By in silico analysis using ASXL2 (612991) as query, Katoh and Katoh (2004) identified full-length human ASXL3. Like other ASX family members, the deduced 2,248-amino acid ASXL3 protein has 2 conserved domains near its N terminus, designated the ASXN and ASXM domains, and a conserved zinc finger plant homeodomain (PHD) at its C terminus. Unlike other ASX proteins, the PHD domain of ASXL3 is preceded by a unique proline-rich region.
Katoh and Katoh (2004) determined that the ASXL3 gene contains 12 exons.
By genomic sequence analysis, Katoh and Katoh (2004) mapped the ASXL3 gene to chromosome 18q12.1, close to the DTNA gene (601239). Katoh and Katoh (2004) noted that the ASXL3-DTNA locus is paralogous to the ASXL2-DTNB (602415) locus on chromosome 2p23.3.
Srivastava et al. (2016) showed that ASXL1 interacts with BAP1 (603089), forming a key component of the polycomb repressive deubiquitination (PR-DUB) complex, which functions to remove the monoubiquitin from lysine-119 of histone H2A (H2AK119Ub1), thus playing a role in chromatin remodeling and transcriptional regulation.
Bainbridge et al. (2013) identified heterozygous nonsense and frameshift mutations in 4 unrelated patients with Bainbridge-Ropers syndrome (BRPS; 615485). All of these mutations occurred de novo in the penultimate exon, in a region analogous to that in ASXL1 (612990) where mutations resulting in Bohring-Opitz syndrome (BOPS; 605039) occur. Bainbridge et al. (2013) reported that database searches revealed truncating mutations in both ASXL1 and ASXL3 5-prime and 3-prime of disease-causing mutations in reportedly phenotypically normal individuals.
In 3 unrelated patients with BRPS, Srivastava et al. (2016) identified 3 de novo heterozygous frameshift or nonsense mutations in the ASXL1 gene (615115.0005-615115.0007). Fibroblasts derived from 1 of the patients with a frameshift mutation in the 5-prime cluster region (c.1448dupT; 615115.0005) showed about a 50% decrease in ASXL1 mRNA and protein levels, consistent with haploinsufficiency. These cells showed significantly increased levels of H2AK119Ub1, indicating that this mutation disrupts the normal activity of the PR-DUB complex. Levels of H3K27me3 were normal. Transcriptome analysis of these cells showed dysregulation of many genes, including those involved in transcriptional regulation, development, and proliferation, as well as in digestive tract development. These findings highlighted a role for dynamic regulation of H2A ubiquitination in development and disease.
In 12 unrelated patients with BRPS, Balasubramanian et al. (2017) identified 12 different de novo heterozygous nonsense or frameshift mutations in the ASXL3 gene (see, e.g., 615115.0006 and 615115.0008). The patients were ascertained from the Deciphering Developmental Disorders (DDD) project, and the mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but all were predicted to result in a loss of function. The authors noted that the mutations reported by Bainbridge et al. (2013) clustered mainly within the 5-prime end of exon 11 between codons 404 and 659. This region lies between the N-terminal protein scaffolding functional domains of the gene and the C-terminal chromatin/DNA-targeting functional domain. Among their cohort, Balasubramanian et al. (2017) noted that 5 of the identified mutations occurred within the original cluster region, whereas 7 occurred 3-prime to this region, suggesting a second cluster region between codons 1045 and 1444.
In a child with Bainbridge-Ropers syndrome (BRPS; 615485), Bainbridge et al. (2013) identified a de novo heterozygous C-to-T transition in the ASXL3 gene that resulted in substitution of a termination codon for glutamine at codon 404 (g.31318578C-T, Q404X). The child had been born small for gestational age at term, developed severe feeding difficulty, had psychomotor delay, and died at the age of 9 months.
In a child with Bainbridge-Ropers syndrome (BRPS; 615485), Bainbridge et al. (2013) identified a de novo heterozygous C-to-T transition in the ASXL3 gene that resulted in substitution of a termination codon for glutamine at codon 466 (g.31318764C-T, Q466X).
In a child with Bainbridge-Ropers syndrome (BRPS; 615485), Bainbridge et al. (2013) identified a de novo heterozygous 4-bp deletion in the ASXL3 gene resulting in frameshift and premature termination (g.31319343_31319346delACAG, Thr659FsTer41). This patient had mild global hypotonia, normal growth, and global developmental delay with intellectual disability and no speech.
In a patient with Bainbridge-Ropers syndrome (BRPS; 615485), Bainbridge et al. (2013) identified a de novo heterozygous single-basepair insertion (T) in the ASXL3 gene that resulted in immediate premature termination (g.31318789_insT, Pro474FsTer0). Brain imaging revealed global mild white matter volume loss with normal myelination, secondary brainstem hypoplasia, and bilateral hypoplasia/dysplasia of cerebellar tonsils. Magnetic resonance spectroscopy was normal.
In a patient with Bainbridge-Ropers syndrome (BRPS; 615485), Srivastava et al. (2016) identified a de novo heterozygous 1-bp duplication (c.1448dupT) in exon 11 of the ASXL3 gene, predicted to result in a frameshift and premature termination (Thr484AsnfsTer5). The mutation occurred within the 5-prime cluster region. Studies of patient fibroblasts showed that the mutation resulted in nonsense-mediated mRNA decay with only 50% expression of normal protein levels.
In a patient with Bainbridge-Ropers syndrome (BRPS; 615485), Srivastava et al. (2016) identified an apparently de novo heterozygous c.4330T-C transition in the ASXL3 gene, resulting in an arg1444-to-ter (R1444X) substitution at the 5-prime end of exon 12. The mutation was found by exome sequencing. The patient's mother did not have the mutation, but the father was unavailable for study. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that this mutation occurs 3-prime to the main cluster region.
Balasubramanian et al. (2017) identified a de novo R1444X mutation in a patient with BRPS and suggested that it may be a recurrent mutation.
In a patient with Bainbridge-Ropers syndrome (BRPS; 615485), Srivastava et al. (2016) identified a de novo heterozygous c.3364C-T transition in the ASXL3 gene, resulting in a gln1122-to-ter (Q1122X) substitution at the 5-prime end of exon 12. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that this mutation occurs 3-prime to the main cluster region.
In a patient with Bainbridge-Ropers syndrome (BRPS; 615485), Balasubramanian et al. (2017) identified a de novo heterozygous c.4144C-T transition in the ASXL3 gene, resulting in a gln1382-to-ter (Q1382X) substitution within the 3-prime cluster region. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.
Bainbridge, M. N., Hu, H., Muzny, D. M., Musante, L., Lupski, J. R., Graham, B. H., Chen, W., Gripp, K. W., Jenny, K., Wienker, T. F., Yang, Y., Sutton, V. R., Gibbs, R. A., Ropers, H. H. De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome. Genome Med. 5: 11, 2013. Note: Electronic Article. [PubMed: 23383720] [Full Text: https://doi.org/10.1186/gm415]
Balasubramanian, M., Willoughby, J., Fry, A. E., Weber, A., Firth, H. V., Deshpande, C., Berg, J. N., Chandler, K., Metcalfe, K. A., Lam, W., Pilz, D. T., Tomkins, S., DDD Study. Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature. J. Med. Genet. 54: 537-543, 2017. [PubMed: 28100473] [Full Text: https://doi.org/10.1136/jmedgenet-2016-104360]
Katoh, M., Katoh, M. Identification and characterization of ASXL3 gene in silico. Int. J. Oncol. 24: 1617-1622, 2004. [PubMed: 15138607]
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]
Srivastava, A., Ritesh, K. C., Tsan, Y.-C., Liao, R., Su, F., Cao, X., Hannibal, M. C., Keegan, C. E., Chinnaiyan, A. M., Martin, D. M., Bielas, S. L. De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. Hum. Molec. Genet. 25: 597-608, 2016. [PubMed: 26647312] [Full Text: https://doi.org/10.1093/hmg/ddv499]