Alternative titles; symbols
HGNC Approved Gene Symbol: ACTL6B
Cytogenetic location: 7q22.1 Genomic coordinates (GRCh38) : 7:100,643,097-100,656,448 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.1 | Developmental and epileptic encephalopathy 76 | 618468 | Autosomal recessive | 3 |
| Intellectual developmental disorder with severe speech and ambulation defects | 618470 | Autosomal dominant | 3 |
The ACTL6B gene encodes a component of the neuron-specific BAF (nBAF) complex in postmitotic neurons. The nBAF complex has a role in chromatin remodeling and histone acetylation, which regulates gene expression during development, particularly in the process of dendritic outgrowth. This complex also contains BRG1 (SMARCA4; 603254) and BRM (SMARCA2; 600014) (summary by Bell et al., 2019).
By searching a database for sequences similar to S. cerevisiae Act3, Harata et al. (1999) obtained cDNAs encoding ACTL6B and ACTL6A (604958), which they called ARPN-alpha and ARPN-beta, respectively. The deduced 426-amino acid ACTL6B protein shares 83% identity with ACTL6A. Both proteins contain an ATP/ADP-binding pocket and 2 potential nuclear localization signals. Fluorescence-tagged ACTL6B was expressed in nuclei of transfected HeLa cells and was excluded from nucleoli. RT-PCR of several human tissues detected ACTL6B in brain only. EST database analysis revealed ACTL6B transcripts in brain and brain-related tissues, including cerebellum, retina, and a teratocarcinoma-derived neuronal cell line. ACTL6B was also present in an alveolar rhabdomyosarcoma.
By RT-PCR of several mouse tissues, Olave et al. (2002) detected Actl6b, which they called Baf53b, in brain only. Immunofluorescence analysis detected Baf53b in neurons from several regions of mouse and rat brain. In mouse embryos, Baf53b was not detected in actively proliferating neural precursors, but it was expressed in postmitotic neurons of the spinal cord and in retinal ganglion neurons, the first neurons to differentiate during retinal development.
Olave et al. (2002) identified mouse Baf53b as a component of brain-specific chromatin remodeling complexes containing the ATPases Brg1 (SMARCA4; 603254) or Brm (SMARCA2; 600014). These complexes appeared distinct from the SWI/SNF-like BAF complexes isolated from non-neuronal cells, such as HeLa cells.
Harata et al. (1999) determined that the ACTL6B gene contains 14 exons.
By genomic sequence analysis, Harata et al. (1999) mapped the ACTL6B gene to chromosome 7q22.
Developmental and Epileptic Encephalopathy 76
In 2 sibs (patients BAB6569 and BAB6570), born of consanguineous parents (family HOU2448), with developmental and epileptic encephalopathy-76 (DEE76; 618468), Karaca et al. (2015) identified a homozygous missense mutation in the ACTL6B gene (R298Q; 612458.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The family was part of a cohort of 128 mostly consanguineous families with neurogenetic disorders who underwent whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 13-month-old girl (patient 17-1447), born of consanguineous parents, with DEE76, Maddirevula et al. (2019) identified a homozygous nonsense mutation in the ACTL6B gene (C333X; 612458.0002). The variant, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was classified as 'likely pathogenic' according to ACMG criteria.
In 2 sibs, born of unrelated Italian parents (family A), with DEE76, Fichera et al. (2019) identified a homozygous nonsense mutation in the ACTL6B gene (Q274X; 612458.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Subsequent screening of a cohort of 85 unrelated patients with a similar disorder identified a Sicilian girl (family B) with a homozygous missense mutation in ACTL6B (G349S; 612458.0004). This mutation segregated with the disorder in the family and was not found in public databases, including gnomAD. Family history revealed that this girl had had a pair of similarly affected monozygotic twin brothers who died at 4 and 5 years of age; DNA was not available from these patients. Functional studies of the variants and studies of patient cells were not performed, but the nonsense variant was predicted to result in nonsense-mediated mRNA decay and a loss of function.
In 11 children from 10 unrelated families with DEE76, Bell et al. (2019) identified homozygous or compound heterozygous mutations in the ACTL6B gene (see, e.g., 612458.0004-612458.0008). The mutations, which were found by exome sequencing from various research and clinical laboratories, were confirmed by Sanger sequencing and segregated with the disorder in the families. Most of the mutations were nonsense, frameshift, or splicing mutations, although 2 French-Canadian families had a homozygous 1-bp deletion that extended the reading frame (Ter427AspextTer33; 612458.0005), 1 family had a homozygous G349S missense variant, 1 had an in-frame deletion (phe147del; 612458.0006), and 2 unrelated patients were compound heterozygous for a missense and a nonsense mutation. The mutations occurred in different domains throughout the gene. Detailed in vitro functional expression studies performed on wildtype human neurons, human neurons with knockdown of the ACTL6B gene, and patient-derived induced human neuronal pluripotent stem cells (iPSCs) carrying the Ter427AspextTer33 mutation showed that ACTL6B is mostly absent from dividing cells, but present in postmitotic neurons mainly after day 5. Patient-derived iPSCs had decreased ACTL6B mRNA, but normal protein levels. The authors noted that the Ter427AspextTer33 mutation escapes nonsense-mediated mRNA decay and that the protein is expressed, whereas other mutations may be subject to nonsense-mediated mRNA decay. Knockdown of ACTL6B in human neurons resulted in almost absent staining for MAP2 (157130), a marker for dendritic development, as well as enlarged nuclear size and delayed neuronal maturation and differentiation; these abnormalities were also observed in Ter427AspextTer33 cells and could be rescued by expression of the wildtype gene. The Ter427AspextTer33 variant showed increased BRG1 (SMARCA4; 603254) binding compared to controls, and this was associated with altered expression of the actin-associated proteins TPPP (608773) and FSCN1 (602689) during early neuronal development. Neuronal induced fibroblasts from another patient with recessive mutations showed similar changes. Expression of certain recessive mutations failed to rescue the phenotype in knockout cells, suggesting that the mutations cause a loss of function. Bell et al. (2019) hypothesized that recessive mutations in ACTLB6 interrupt the dynamic of the BAF complex, resulting in impaired neuronal differentiation and dendritic formation. The findings indicated the importance of chromatin remodeling machinery in brain disease.
Intellectual Developmental Disorder With Severe Speech And Ambulation Defects
In 9 unrelated patients with intellectual developmental disorder with severe speech and ambulation defects (IDDSSAD; 618470), Bell et al. (2019) identified the same de novo heterozygous missense mutation in the ACTL6B gene (G343R; 612458.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro cellular functional expression studies indicated that the G343R variant behaved like the wildtype protein in activating markers of ACTL6B function, suggesting to the authors that it may confer unknown gain-of-function effects rather than resulting in haploinsufficiency. Another patient with IDDSSAD carried a de novo heterozygous D77G mutation (612458.0010), also predicted to result in a gain-of-function effect, possibly by interfering with the ability of ACTL6B to interact with other proteins.
Wu et al. (2007) found that Baf53b -/- mice developed normally in utero and were born at the expected mendelian ratio with normal morphology, but that most died by postnatal day-2 (P2), likely due to failure to nurse. In a mixed genetic background between 129/sv and C57BL/6 strains, about 25% of Baf53b -/- mice survived beyond P2, and about 12% survived to adulthood. Baf53b -/- mice that escaped perinatal lethality were extremely hyperactive, suggesting neural developmental abnormalities. Examination of Baf53b -/- adult mouse brain revealed normal assembly of nBAF complexes, indicating that assembly is Baf53b independent. However, nBAF function was Baf53b dependent and was required for dendritic development, as loss of Baf53b resulted in reduced dendritic length and complexity in neurons. Loss of Baf53b also led to abnormal axonal development in neurons. Coimmunoprecipitation and chromatin immunoprecipitation analyses demonstrated that nBAF complexes interacted with Crest (SS18L1; 606472) to regulate expression of ephexin-1 (NGEF; 605991). Baf53b was not required for nBAF-Crest interaction, but was it required for targeting of nBAF complexes and Crest to promoters to promote dendritic outgrowth. Baf53a could not replace Baf53b in dendritic development, and the authors determined that this functional specificity was due to the divergent subdomain-2 within the actin fold of Baf53b.
Vogel-Ciernia et al. (2013) found that anxiety and motor function were normal in Baf53b +/- mice and in transgenic mice expressing Baf53b with a deletion of the hydrophobic domain. However, both mutant mouse lines showed impairment in long-term memory for contextual fear, whereas cued fear memory was normal. Reintroduction of Baf53b into dorsal hippocampus of adult mutant mice rescued memory for object location, but not memory for object recognition. Further examination of mutant mouse hippocampus demonstrated that Baf53b was required for consolidation of lasting changes in synaptic strength and suggested that Baf53b played roles in spine morphology/structure and synaptic function. RNA sequencing analysis demonstrated that Baf53b-dependent gene expression related to functional and structural foundations of long-term memory was disrupted in Baf53b mutant mice during memory consolidation, resulting in the observed defects.
In 2 sibs (patients BAB6569 and BAB6570), born of consanguineous parents (family HOU2448), with developmental and epileptic encephalopathy-76 (DEE76; 618468), Karaca et al. (2015) identified a homozygous c.893G-A transition (c.893G-A, NM_016188) in exon 10 of the ACTL6B gene, resulting in an arg298-to-gln (R298Q) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In a 13-month-old girl (patient 17-1447), born of consanguineous parents, with developmental and epileptic encephalopathy-76 (DEE76; 618468), Maddirevula et al. (2019) identified a homozygous c.999T-A transversion (c.999T-A, NM_016188.4) in the ACTL6B gene, resulting in a cys333-to-ter (C333X) substitution. The variant, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was classified as 'likely pathogenic' according to ACMG criteria.
In 2 sibs, born of unrelated Italian parents (family A), with developmental and epileptic encephalopathy-76 (DEE76; 618468), Fichera et al. (2019) identified a homozygous c.820C-T transition (c.820C-T, NM_016188) in the ACTL6B gene, resulting in a gln274-to-ter (Q274X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the dbSNP, 1000 Genomes Project, Exome Sequencing Project, ExAC, and gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in nonsense-mediated mRNA decay and a loss of function. The patients presented with severe refractory seizures in the first week of life. They had poor overall growth and achieved few developmental milestones.
In a 4-year-old Sicilian girl, born of unrelated parents (family B) with developmental and epileptic encephalopathy-76 (DEE76; 618468), Fichera et al. (2019) identified a homozygous c.1045G-A transition (c.1045G-A, NM_016188) in the ACTL6B gene, resulting in a gly349-to-ser (G349S) substitution at a highly conserved residue. The mutation, which was found by next-generation sequencing of a candidate epilepsy gene panel, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases, or in 850 ethnically matched controls. Functional studies of the variant and studies of patient cells were not performed. She developed epileptic spasms at 2 months of age. Family history revealed that the proband had had a pair of similarly affected monozygotic twin brothers who died at 4 and 5 years of age; DNA from these sibs was not available.
In 3 patients from 2 unrelated French-Canadian families (R3 and R10) with developmental and epileptic encephalopathy-76 (DEE76; 618468), Bell et al. (2019) identified a homozygous 1-bp deletion (c.1279del, NM_016188.4) in the ACTL6B gene, resulting in a frameshift and extension of the reading frame by 33 additional amino acids (Ter427AspextTer33). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. It was not found in the gnomAD database. The findings suggested that the families may be related, although this was not confirmed. In vitro functional expression studies in human induced pluripotent stem cells (iPSC) programmed into neuronal cells showed that the mutant cells had features that recapitulated those observed in cells with knockdown of the ACTL6B gene, including deficits in dendrite development, consistent with a loss of function. The patients developed seizures in the first months of life.
In a 3-year-old girl (patient R1) with developmental and epileptic encephalopathy-76 (DEE76; 618468), Bell et al. (2019) identified a homozygous 3-bp in-frame deletion (c.441delCTT, NM_016188.4) in the ACTL6B gene, resulting in the deletion of residue phe147 (phe147del). The mutation was found at a low frequency in the heterozygous state in the gnomAD database (1.4 x 10(-5)). The patient developed myoclonic seizures at 3 months of age.
In a 14-month-old girl (patient R9) with developmental and epileptic encephalopathy-76 (DEE76; 618468), Bell et al. (2019) identified compound heterozygous mutations in the ACTL6B gene: a c.724C-T transition (c.724C-T, NM_016188.4), resulting in a gln242-to-ter (Q242X) substitution, and a c.617T-C transition, resulting in a leu206-to-pro substitution (L206P; 612458.0008). Neither mutation was found in the gnomAD database. In vitro functional expression studies in human induced pluripotent stem cells (iPSC) programmed into neuronal cells showed that the mutant cells had features that recapitulated those observed in cells with knockdown of the ACTL6B gene, including deficits in dendrite development, consistent with a loss of function. The patient presented in the prenatal period with myoclonic and tonic seizures.
For discussion of the c.617T-C transition (c.617T-C, NM_016188.4) in the ACTL6B gene, resulting in a leu206-to-pro (L206P) substitution, that was found in compound heterozygous state in a patient with developmental and epileptic encephalopathy-76 (DEE76; 618468) by Bell et al. (2019), see 612458.0007.
In 9 unrelated patients with intellectual developmental disorder with severe speech and ambulation defects (IDDSSAD; 618470), Bell et al. (2019) identified the same de novo heterozygous c.1027G-A transition (c.1027G-A, NM_016188.4) in exon 12 of the ACTL6B gene, resulting in a gly343-to-arg (G343R) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro cellular functional expression studies indicated that the G343R variant behaved like the wildtype protein in activating markers of ACTL6B function, suggesting to the authors that it may confer unknown gain-of-function effects rather than resulting in haploinsufficiency.
In an 8-year-old girl (patient D9) with intellectual developmental disorder with severe speech and ambulation defects (IDDSSAD; 618470), Bell et al. (2019) identified a de novo heterozygous c.230A-G transition (c.230A-G, NM_016188.4) in exon 3 of the ACTL6B gene, resulting in an asp77-to-gly (D77G) substitution at a conserved residue. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the authors predicted that the mutation would result in a gain-of-function effect.
Bell, S., Rousseau, J., Peng, H., Aouabed, Z., Priam, P., Theroux, J.-F., Jefri, M., Tanti, A., Wu, H., Kolobova, I., Silviera, H., Manzano-Vargas, K., and 57 others. Mutations in ACTL6B cause neurodevelopmental deficits and epilepsy and lead to loss of dendrites in human neurons. Am. J. Hum. Genet. 104: 815-834, 2019. [PubMed: 31031012] [Full Text: https://doi.org/10.1016/j.ajhg.2019.03.022]
Fichera, M., Failla, P., Saccuzzo, L., Miceli, M., Salvo, E., Castiglia, L., Galesi, O., Grillo, L., Cali, F., Greco, D., Amato, C., Romano, C., Elia, M. Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy. Hum. Genet. 138: 187-198, 2019. [PubMed: 30656450] [Full Text: https://doi.org/10.1007/s00439-019-01972-3]
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]
Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others. Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease. Neuron 88: 499-513, 2015. [PubMed: 26539891] [Full Text: https://doi.org/10.1016/j.neuron.2015.09.048]
Maddirevula, S., Alzahrani, F., Al-Owain, M., Al Muhaizea, M. A., Kayyali, H. R., AlHashem, A., Rahbeeni, Z., Al-Otaibi, M., Alzaidan, H. I., Balobaid, A., El Khashab, H. Y., Bubshait, D. K., and 36 others. Autozygome and high throughput confirmation of disease genes candidacy. Genet. Med. 21: 736-742, 2019. [PubMed: 30237576] [Full Text: https://doi.org/10.1038/s41436-018-0138-x]
Olave, I., Wang, W., Xue, Y., Kuo, A., Crabtree, G. R. Identification of a polymorphic, neuron-specific chromatin remodeling complex. Genes Dev. 16: 2509-2517, 2002. [PubMed: 12368262] [Full Text: https://doi.org/10.1101/gad.992102]
Vogel-Ciernia, A. Matheos, D. P., Barrett, R. M., Kramar, E. A., Azzawi, S., Chen, Y., Magnan, C. N., Zeller, M., Sylvain, A., Haettig, J., Jia, Y., Tran, A., and 10 others. The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nature Neurosci. 16: 552-561, 2013. [PubMed: 23525042] [Full Text: https://doi.org/10.1038/nn.3359]
Wu, J. I., Lessard, J., Olave, I. A., Qiu, Z., Ghosh, A., Graef, I. A., Crabtree, G. R. Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56: 94-108, 2007. [PubMed: 17920018] [Full Text: https://doi.org/10.1016/j.neuron.2007.08.021]