Alternative titles; symbols
HGNC Approved Gene Symbol: ACTL6A
Cytogenetic location: 3q26.33 Genomic coordinates (GRCh38) : 3:179,562,926-179,588,407 (from NCBI)
The SWI/SNF complex in S. cerevisiae and Drosophila is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. The complex contains an ATP-dependent nucleosome disruption activity that can lead to enhanced binding of transcription factors. The BRG1/brm (603254)-associated factor (BAF) complex in mammals is functionally related to SWI/SNF and consists of 9 to 12 subunits, some of which are homologous to SWI/SNF subunits. Zhao et al. (1998) purified a 53-kD BAF subunit, which they called BAF53, from extracts of a human cell line and obtained a partial protein sequence. Based on the peptide sequences, they isolated a cDNA encoding BAF53. The 429-amino acid BAF53 protein shares extensive amino acid homology with actin (see 102540) and the yeast actin-related proteins Act2 and Act3. In addition, sequences encoding BAF53 homologs were identified in yeast and C. elegans. Two of 3 amino acids (asp11, gln137, and asp154 in actin) involved in tight calcium binding are conserved (asp17 and asp171 in BAF53). In contrast with the overall homology to actin, the ATP-binding pocket in actin is poorly conserved in BAF53, suggesting that BAF53 may not have ATP-binding activity. A comparison of the sequences of actin family members revealed that BAF53 is most related to Arp3, which is involved in Listeria motility.
By searching a database for sequences similar to S. cerevisiae Act3, Harata et al. (1999) obtained cDNAs encoding ACTL6A and ACTL6B (612458), which they called ARPN-beta and ARPN-alpha, respectively. The deduced 429-amino acid ACTL6A protein shares 83% identity with ACTL6B. Both proteins contain an ATP/ADP-binding pocket and 2 potential nuclear localization signals. Fluorescence-tagged ACTL6A was expressed in nuclei of transfected HeLa cells and was excluded from nucleoli. RT-PCR of human tissues detected wide ACTL6A expression, which was confirmed by EST database analysis.
Zhao et al. (1998) demonstrated that beta-actin (102630) and BAF53 are required for maximal ATPase activity of BRG1 and are also required with BRG1 for association of the BAF complex with chromatin/matrix.
The NuA4 histone acetyltransferase (HAT) complex is responsible for acetylation of the N-terminal tails of histone H4 (see 602822) and H2A (see 613499) in yeast. Its catalytic subunit, Esa1, is homologous to human TIP60 (HTATIP; 601409). Using affinity purification, Western blot analysis, cell fractionation, immunoprecipitation, and mass spectrometry, Doyon et al. (2004) found that TIP60 and its splice variant, TIP60B/PLIP, were part of a multisubunit NuA4 complex with HAT activity in several human cell lines. They identified human homologs for 11 of the 12 yeast NuA4 subunits, including BAF53A.
At the point of mitotic exit within the vertebrate nervous system, when cells lose multipotency and begin to develop stable connections that will persist over life, a switch in ATP-dependent chromatin-remodeling mechanisms occurs. This switch involves the exchange of the BAF53A and BAF45A (PHF10; 613069) subunits within Swi/Snf-like neural progenitor-specific BAF (npBAF) complexes for the homologous BAF53B (ACTL6B; 612458) and BAF45B (DPF1; 601670) subunits within neuron-specific BAF (nBAF) complexes in postmitotic neurons. The subunits of the npBAF complex are essential for neural progenitor proliferation, and mice with reduced dosage for the genes encoding its subunits have defects in neural tube closure similar to those in human spina bifida. In contrast, BAF53B and the nBAF complex are essential for an evolutionarily conserved program of postmitotic neural development and dendritic morphogenesis. Yoo et al. (2009) showed that this essential transition is mediated by repression of BAF53A by miR9* (an miRNA processed from the opposite arm of the miR9 (611186) stem-loop precursor) and miR124 (609327). They found that BAF53a repression is mediated by sequences in the 3-prime untranslated region corresponding to the recognition sites for miR9* and miR124, which are selectively expressed in postmitotic neurons. Mutation of these sites led to persistent expression of BAF53A and defective activity-dependent dendritic outgrowth in neurons. In addition, overexpression of miR9* and miR124 in neural progenitors caused reduced proliferation. Previous studies indicated that miR9* and miR124 are repressed by the repressor element-silencing transcription factor (REST; 600571). Yoo et al. (2009) showed that expression of REST in postmitotic neurons led to derepression of BAF53a, indicating that REST-mediated repression of microRNAs directs the essential switch of chromatin regulatory complexes.
Associations Pending Confirmation
Marom et al. (2017) reported 3 unrelated patients with varying degrees of developmental delay and mild anomalies who had heterozygous variants in the ACTL6A gene; trio whole-exome sequencing (WES) performed for patients 1 and 3 found that the pathogenic variants occurred de novo. Patient 1, a 15-year-old girl who had previously been reported by Brautbar et al. (2009), had an arg377-to-trp (R377W; 604958.0001) substitution at a conserved residue. Patient 2, a 6-year-old boy with developmental delay, attention deficit-hyperactivity disorder (ADHD), and other behavioral problems, had a g.179,294,612G-C transversion (NC_000003.11) in exon 8, resulting in a glu227-to-gln (E227Q) substitution at a conserved residue. Hamosh (2024) noted that the E227Q mutation in ACTL6A was present in 45 of 1,613,786 alleles, in heterozygosity only, in the gnomAD database (v4.0), for an allele frequency of 2.8 x 10(-5). The mother was negative for the variant, but the father, who had a history of ADHD and learning disability, was not available for testing. Patient 2 was born prematurely. He had articulation problems, poor fine motor skills, and sensory integration deficits. At age 5 years, he had borderline intelligence but failure to thrive had resolved. He had a narrow face, prominent forehead, and poorly developed philtrum. He had fifth finger clinodactyly, partial 3-4 finger syndactyly, and 2-3 toe syndactyly. He required surgery to repair umbilical and bilateral inguinal hernias. Both parents had learning disabilities. Patient 3, a 6-year-old boy born at 35 weeks with hydronephrosis due to posterior urethral valves, glanular hypospadias, and laryngomalacia, had a de novo splice site mutation (c.1209+1G-C, NM_004301.3) in intron 13, resulting in in-frame deletion of exon 13. The variant was not found in the ExAC or 1000 Genomes Project databases. Western blot analysis showed decreased protein expression in patient cells, and cell cycle analysis showed a smaller fraction of patient cells residing in G2 phase compared to control cells. Patient 3 walked at 15 months and had first words at 12 months, but at age 6 years, he had an IQ of 56. Facial dysmorphic features included high forehead, low-set everted ears, and narrow palpebral fissures. Feet showed overriding second toe, clinodactyly of toes 3, 4, and 5, and sandal gap.
Pascolini et al. (2020) identified the R377W variant in an Italian boy with developmental delay and dysmorphic facies.
Chen et al. (2022) reported 2 additional patients with heterozygous de novo missense variants, pro126-to-leu (P126L) and arg389-to-trp (R389W), in the ACTL6A gene. Very little phenotypic information was provided, but the patients were described as having a neurodevelopmental disorder. Hamosh (2024) found each of the variants 1 time in the gnomAD database (v4.0).
In a Chinese boy diagnosed with heart-hand syndrome (patent ductus arteriosus, persistent left superior vena cava, and congenital absence of the left arm radius) and craniofacial anomalies, Yuan et al. (2021) identified a heterozygous de novo single-nucleotide deletion, c.478delT (NM_004301), in the ACTL6A gene, resulting in frameshift and premature termination (Phe160LeufsTer9). He had mild short stature and intellectual disability (IQ of 59). No functional studies were performed. Hamosh (2024) noted that this variant was absent from the gnomAD database (v4.0).
This variant is classified as a variant of unknown significance because its contribution to syndromic impaired intellectual development has not been confirmed.
In a 15-year-old girl, previously reported by Brautbar et al. (2009) as having brachymorphism-onychodysplasia-dysphalangism syndrome (113477) or Coffin-Siris syndrome (see 135900), Marom et al. (2017) identified a de novo heterozygous g.179,304,340C-T transition (NC_000003.11) in exon 13 of the ACTL6A gene, resulting in an arg377-to-trp (R377W) substitution at a conserved residue. She presented with developmental delay that involved speech and language difficulties and attention problems. She had to repeat first grade and continued to have significant learning difficulties in school. She had atrial septal defect and cleft mitral valve that required surgical repair. She also had torticollis, gastroesophageal reflux, recurrent ear infections, and urinary bladder irritability, all of which resolved during childhood. She underwent surgical repair of bilateral inguinal and umbilical hernias. Dysmorphic features included coarse facies, bushy eyebrows, prominent ears, and broad nasal tip. She had hypoplastic nails on multiple digits, unusually broad thumbs, and mildly persistent fetal fingertip pads.
Pascolini et al. (2020) reported the second occurrence of a de novo heterozygous c.1129C-T transition (c.1129C-T, NM_004301.5) in an 8-year-old Italian boy. He was born after a 37-week, 6-day gestation complicated by intrauterine growth restriction and had a postnatal pneumothorax of unknown etiology. Cryptorchidism and umbilical hernia were repaired at age 5 years. He had severe constipation. On examination at age 7, he had hypertrichosis, but sparse, thin scalp hair, coarse facial features, thick eyebrows, long and prominent eyelashes, bulbous nose with enlarged nostrils and low-hanging columella, smooth philtrum, thin upper lip, thick lower lip, and wide mouth. Brachydactyly was present with prominent interphalangeal joints, broad distal thumb, and hypoplastic nails throughout, with no nails on fifth toes. X-rays showed absent distal phalanx on fifth toes bilaterally. Brain MRI showed short, thick corpus callosum. He manifested developmental delay and had severe sleep disturbance. Growth parameters were in the normal range.
Hamosh (2024) identified the R377W variant in gnomAD (v.4.0) in 5 of 1,581,764 alleles, in heterozygosity only, for an allele frequency of 3.2 x 10(-6).
Brautbar, A., Ragsdale, J., Shinawi, M. Is this the Coffin-Siris syndrome or the BOD syndrome? (Letter) Am. J. Med. Genet. 149A: 559-562, 2009. [PubMed: 19215055] [Full Text: https://doi.org/10.1002/ajmg.a.32671]
Chen, C.-A., Lattier, J., Zhu, W., Rosenfeld, J., Wang, L., Scott, T. M., Du, H., Patel, V., Dang, A., Magoulas, P., Streff, H., Sebastian, J., and 19 others. Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies. Genet. Med. 24: 364-373, 2022. [PubMed: 34906496] [Full Text: https://doi.org/10.1016/j.gim.2021.09.017]
Doyon, Y., Selleck, W., Lane, W. S., Tan, S., Cote, J. Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans. Molec. Cell. Biol. 24: 1884-1896, 2004. [PubMed: 14966270] [Full Text: https://doi.org/10.1128/MCB.24.5.1884-1896.2004]
Hamosh, A. Personal Communication. Baltimore, Md. 03/20/2024.
Harata, M., Mochizuki, R., Mizuno, S. Two isoforms of a human actin-related protein show nuclear localization and mutually selective expression between brain and other tissues. Biosci. Biotech. Biochem. 63: 917-923, 1999. [PubMed: 10380635] [Full Text: https://doi.org/10.1271/bbb.63.917]
Marom, R., Jain, M., Burrage, L., Song, I.-W., Graham, B. H., Brown, C. W., Stevens, S. J. C., Stegmann, A. P. A., Gunter, A. T., Kaplan, J. D., Gavrilova, R. H., Shinawi, M., and 12 others. Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. Hum. Mutat. 38: 1365-1371, 2017. [PubMed: 28649782] [Full Text: https://doi.org/10.1002/humu.23282]
Pascolini, G., Agolini, E., Novelli, A., Majore, S., Grammatico, P. The p.Arg377Trp variant in ACTL6A underlines a recognizable BAF-opathy phenotype. Clin. Genet. 97: 672-674, 2020. [PubMed: 31994175] [Full Text: https://doi.org/10.1111/cge.13682]
Yoo, A. S., Staahl, B. T., Chen, L., Crabtree, G. R. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460: 642-646, 2009. Note: Erratum: Nature 461: 296 only, 2009. [PubMed: 19561591] [Full Text: https://doi.org/10.1038/nature08139]
Yuan, Z.-Z., Xie, X.-H., Gu, H., Zhang, W.-Z., Hu, Y.-Q., Yang, Y.-F., Tan, Z.-P. Case report: BAF-opathies/SSRIDDs due to a de novo ACTL6A variant, previously considered to be heart-hand syndrome. Front. Cardiovasc. Med. 8: 708033, 2021. [PubMed: 34485408] [Full Text: https://doi.org/10.3389/fcvm.2021.708033]
Zhao, K., Wang, W., Rando, O. J., Xue, Y., Swiderek, K., Kuo, A., Crabtree, G. R. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95: 625-636, 1998. [PubMed: 9845365] [Full Text: https://doi.org/10.1016/s0092-8674(00)81633-5]