Alternative titles; symbols
HGNC Approved Gene Symbol: ACTB
SNOMEDCT: 239144007, 5387003, 878889000;
Cytogenetic location: 7p22.1 Genomic coordinates (GRCh38): 7:5,527,148-5,530,601 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p22.1 | Baraitser-Winter syndrome 1 | 243310 | Autosomal dominant | 3 |
| Becker nevus, syndromic or isolated, somatic mosaic | 604919 | 3 | ||
| Congenital smooth muscle hamartoma with or without hemihypertrophy, somatic mosaic | 620479 | 3 | ||
| Dystonia-deafness syndrome 1 | 607371 | Autosomal dominant | 3 | |
| Thrombocytopenia 8, with dysmorphic features and developmental delay | 620475 | Autosomal dominant | 3 |
The ACTB gene encodes beta-actin, which is essential for a number of cytoplasmic functions, such as regulation of cell shape and migration, as well as nuclear functions, such as regulation of gene expression, cell division, and proliferation (summary by Cuvertino et al., 2017).
From studies of the amino acid sequence of cytoplasmic and muscle actins, Vandekerckhove and Weber (1978) concluded that mammalian cytoplasmic actins are the products of 2 different genes and differ by many amino acids from muscle actin. In a neoplastic cell line resulting from treatment of cultured human diploid fibroblasts with a chemical mutagen, Leavitt et al. (1982) observed a mutant form of beta-actin. Toyama and Toyama (1984) isolated and characterized lines of KB cells resistant to cytochalasin B. They found that one resistant line had an alteration in beta-actin. Such cells bound less cytochalasin B than did parental KB cells. The authors suggested that the primary site of action of cytochalasin B on cell motility processes is beta-actin.
Using chick beta-actin cDNA as probe, Gunning et al. (1983) cloned beta-actin and gamma-actin (ACTG1; 102560) from a fibroblast cDNA library. They noted that the N-terminal methionine is posttranslationally removed from the mature beta- and gamma-actin proteins.
In embryonic mouse tissue at day 14, Cuvertino et al. (2017) found prominent expression of the Actb gene in cortical neurons and choroid plexus epithelia in the brain, in differentiating tubules of the metanephric kidney, and in the epicardium, endocardium, and muscle in the outflow tract of the heart.
Latham et al. (2018) stated that the ACTB gene contains 6 exons.
Ng et al. (1985) assigned the ACTB gene to 7pter-q22 by Southern blot analysis of DNA from somatic cell hybrids. Habets et al. (1992) generated hybrids that harbor only specific regions of human chromosome 7 and assigned the ACTB locus to 7p15-p12.
Ueyama et al. (1996) used fluorescence in situ hybridization to map ACTB to 7p22. By PCR of somatic cell hybrid DNAs, they mapped 4 ACTB pseudogenes to other chromosomes.
Interaction of phospholipase D (see PLD1; 602382) with actin microfilaments regulates cell proliferation, vesicle trafficking, and secretion. Kusner et al. (2002) found that highly purified globular actin (G-actin) inhibited both basal and stimulated PLD1 activity, whereas filamentous actin (F-actin) had the opposite effect. Actin-induced modulation of PLD1 activity was independent of the activating stimulus. The effects of actin on PLD1 were isoform-specific: human platelet actin, which exists in a 5:1 ratio of beta- and gamma-actin, was only 45% as potent and 40% as efficacious as rabbit skeletal muscle alpha-actin.
Localization of beta-actin mRNA to sites of active actin polymerization modulates cell migration during embryogenesis, differentiation, and possibly carcinogenesis. This localization requires the oncofetal protein ZBP1 (608288), which binds to a conserved 54-nucleotide element in the 3-prime untranslated region of the beta-actin mRNA known as the 'zipcode.' ZBP1 promotes translocation of the beta-actin transcript to actin-rich protrusions in primary fibroblasts and neurons. Huttelmaier et al. (2005) showed that chicken ZBP1 modulates the translation of beta-actin mRNA. ZBP1 associates with the beta-actin transcript in the nucleus and prevents premature translation in the cytoplasm by blocking translation initiation. Translation occurs only when the ZBP1-RNA complex reaches its destination at the periphery of the cell. At the endpoint of mRNA transport, the protein kinase Src (190090) promotes translation by phosphorylating a key tyrosine residue in ZBP1 that is required for binding to RNA. These sequential events provide both temporal and spatial control over beta-actin mRNA translation, which is important for cell migration and neurite outgrowth.
In immunoprecipitation studies of embryonic fibroblasts from wildtype and knockout mice deficient in the arginylation enzyme Ate1 (607103), Karakozova et al. (2006) found that approximately 40% of intracellular beta-actin is arginylated in vivo. In both wildtype and Ate1-null cells beta-actin was stable, suggesting that arginylation does not induce beta-actin degradation. Karakozova et al. (2006) found that arginylation of beta-actin regulates cell motility. The majority of Ate1-null cells appeared smaller than wildtype cells and were apparently unable to form a lamella during movement along the substrate. In addition, Ate1-null cells exhibited apparent defects in ruffling activity and cortical flow. Karakozova et al. (2006) concluded that arginylation of beta-actin apparently represents a critical step in the actin N-terminal processing needed for actin functioning in vivo.
Nitric oxide (NO) is a paracrine mediator of vascular and platelet function that is produced in the vasculature by NO synthase-3 (NOS3; 163729). Using human platelets, Ji et al. (2007) demonstrated that polymerization of beta-actin regulated the activation state of NOS3, and hence NO formation, by altering its binding to heat-shock protein-90 (HSP90, or HSPCA; 140571). NOS3 bound the globular, but not the filamentous, form of beta-actin, and the affinity of NOS3 for globular beta-actin was, in turn, increased by HSP90. Formation of this ternary complex of NOS3, globular beta-actin, and HSP90 increased NOS activity and cyclic GMP, an index of bioactive NO, and increased the rate of HSP90 degradation, thus limiting NOS3 activation. Ji et al. (2007) concluded that beta-actin regulates NO formation and signaling in platelets.
The mammalian cytoskeletal proteins beta- and gamma-actin are highly homologous, but only beta-actin is N-terminally arginylated in vivo, which regulates its function. Zhang et al. (2010) examined the metabolic fate of exogenously expressed arginylated and nonarginylated actin isoforms. Arginylated gamma-actin, unlike beta-actin, was highly unstable and was selectively ubiquitinated and degraded in vivo. This instability was regulated by the differences in the nucleotide coding sequence between the 2 actin isoforms, which conferred different translation rates. Gamma-actin was translated more slowly than beta-actin, and this slower processing resulted in the exposure of a normally hidden lysine residue for ubiquitination, leading to the preferential degradation of gamma-actin upon arginylation. Zhang et al. (2010) suggested that this degradation mechanism, coupled to nucleotide coding sequence, may regulate protein arginylation in vivo.
Glinka et al. (2010) noted that the beta-actin mRNA binding protein HNRNPR (607201) has been identified as a partner of the survival motor neuron protein (SMN1; 600354) that is deficient in spinal muscular atrophy. They reported that hnRNPR and beta-actin mRNA colocalized in axons. Recombinant hnRNPR interacted directly with the 3-prime UTR of beta-actin mRNA. Suppression of hnRNPR in developing zebrafish embryos resulted in reduced axon growth in spinal motor neurons, without any alteration in motor neuron survival. ShRNA-mediated knockdown in isolated embryonic mouse motor neurons reduced beta-actin mRNA translocation to the axonal growth cone, which was paralleled by reduced axon elongation. Dendrite growth and neuronal survival were not affected by hnRNPR depletion in these neurons. The loss of beta-actin mRNA in axonal growth cones of hnRNPR-depleted motor neurons resembled that observed in Smn-deficient motor neurons, a model for the human disease spinal muscular atrophy. In particular, hnRNPR-depleted motor neurons also exhibited defects in presynaptic clustering of voltage-gated calcium channels. Glinka et al. (2010) suggested that hnRNPR-mediated axonal beta-actin mRNA translocation may play an essential physiologic role in axon growth and presynaptic differentiation.
Buxbaum et al. (2014) used single-molecule in situ hybridization to demonstrate that dendritic beta-actin mRNA and ribosomes are in a masked, neuron-specific form. Chemically induced long-term potentiation prompts transient mRNA unmasking, which depends on factors active during synaptic activity. Ribosomes and single beta-actin mRNA motility increase after stimulation, indicative of release from complexes. Buxbaum et al. (2014) argued that their single-molecule assays allow for the quantification of activity-induced unmasking and availability for active translation, and that their work demonstrates that beta-actin mRNA and ribosomes are in a masked state that is alleviated by stimulation.
Pseudogenes
Ng et al. (1985, 1985) showed that there are about 20 pseudogenes widely distributed in the genome. ACTBP1 is on Xq13-q22; ACTBP2, on chromosome 5; ACTBP3, on chromosome 18; ACTBP4, on chromosome 5 and ACTBP5, on 7q22-7qter. All have been mapped in somatic cell hybrids by use of DNA clones.
Dystonia-Deafness Syndrome 1
In the monozygotic twins reported by Gearing et al. (2002) with dystonia-deafness syndrome-1 (DDS1; 607371), Procaccio et al. (2006) identified a heterozygous missense mutation in the ACTB gene (R183W; 102630.0001). The disease phenotype included developmental midline malformations, sensory hearing loss, and a delayed-onset generalized dystonia syndrome. Cellular studies of a lymphoblastoid cell line obtained from an affected patient demonstrated morphologic abnormalities of the actin cytoskeleton and altered actin depolymerization dynamics in response to latrunculin A, an actin monomer-sequestering drug. Resistance to latrunculin A was also observed in NIH 3T3 cells expressing the mutant actin. These findings suggested that mutations in nonmuscle actins may be associated with a broad spectrum of developmental malformations and/or neurologic abnormalities such as dystonia. Riviere et al. (2012) suggested that this report should be interpreted with caution given the absence of replication studies and unavailability of parental DNA.
In a 15-year-old boy, born of consanguineous Hutterite parents, with DDS1, Conboy et al. (2017) identified a de novo heterozygous R183W mutation in the ACTB gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in several public databases, including the Exome Sequencing Project and ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In a 22-year-old woman with DDS1, Skogseid et al. (2018) identified heterozygosity for the R183W mutation in the ACTB gene. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 52-year-old Brazilian woman with DDS1, Freitas et al. (2020) identified heterozygosity for the R183W mutation in the ACTB gene. The mutation was identified by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 34-year-old Argentinian woman with DDS1, Zavala et al. (2022) identified heterozygosity for the R183W mutation in the ACTB gene. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.
Baraitser-Winter Syndrome 1
Riviere et al. (2012) identified heterozygous missense mutations in 10 of 18 patients with Baraitser-Winter syndrome-1 (BRWS1; 243310). In all cases in which parental DNA was available, the mutation was shown to have occurred de novo. Seven of the 10 patients carried a recurrent arg196-to-his mutation (R1906H; 102630.0002). One carried a different mutation at the same codon, arg196-to-cys (102630.0003), and the other 2 patients carried different de novo missense mutations in the ACTB gene (102630.0004-102630.0005).
In a 7-year-old girl with atypical Baraitser-Winter syndrome-1, who did not exhibit lissencephaly or seizures, Johnston et al. (2013) identified a de novo missense mutation in the ACTB gene (E117K; 102630.0006).
In 3 patients with a diagnosis of Fryns-Aftimos syndrome, Di Donato et al. (2014) identified mutations in the ACTB gene; see, e.g., R196C (102630.0003), a recurrent mutation in patients with BRWS, and T120I (102630.0007). On the basis of the ACTB mutations and analysis of the clinical findings, the authors reclassified the diagnosis of these patients as severe BRWS. In 2 patients with a severe BRWS phenotype, who were previously diagnosed with cerebrofrontofacial syndrome (Guion-Almeida and Richieri-Costa, 1992; Guion-Almeida and Richieri-Costa, 1999), Verloes et al. (2015) identified the T120I mutation. Verloes et al. (2015) suggested that this mutation is associated with a severe phenotype.
In 3 unrelated patients (XXIV, XXV, and XXVI) with a pleiotropic developmental disorder similar to BRWS1, Cuvertino et al. (2017) identified de novo heterozygous loss-of-function frameshift or nonsense mutations in the ACTB gene (102630.0008-102630.0010), consistent with haploinsufficiency. Cuvertino et al. (2017) also reported 30 patients from 23 unrelated families with a similar pleiotropic developmental disorder associated with heterozygous larger deletions of chromosome 7p22, all of which included or putatively affected the ACTB gene as well as additional genes. The deletions, which had different breakpoints, ranged from 0.08 to 3.64 Mb in size, and ACTB was the only gene deleted within the minimal critical region. Cells from 4 patients with larger deletions showed reduced ACTB transcript levels compared to controls. Although cytoplasmic levels of beta-actin protein in patient fibroblasts were similar to controls, the ACTB-deficient cells were significantly more circular compared to control cells; ACTB-deficient cells also showed impaired migration in an in vitro wound assay. Similar results were obtained in control fibroblasts using siRNA-mediated ACTB gene silencing. Cells derived from deletion patients showed decreased nuclear ACTB protein levels, abnormal regulation and expression of genes involved in the cell cycle, and decreased cellular proliferation. Cuvertino et al. (2017) noted that the partial overlap of phenotypes of individuals with BRWS resulting from heterozygous ACTB missense mutations and those resulting from loss-of-function mutations suggested that the disorder may result not only from a postulated gain-of-function mechanism, as suggested by Riviere et al. (2012), but might also include effects resulting from a loss-of-function or dominant-negative mechanism. The findings suggested that the phenotype resulted from haploinsufficiency of the ACTB gene, which plays a role in development, particularly of the brain, heart, and kidney.
Becker Nevus Syndrome and Becker Nevi
In a 13-year-old girl with Becker nevus syndrome (BNS; 604919), Cai et al. (2017) performed exome sequencing of affected and nonaffected skin and identified heterozygosity for a missense mutation in the ACTB gene (R147C; 102630.0011) in lesional skin that was absent from adjacent normal skin. Analysis of 22 nonsyndromic Becker nevi (BN) revealed that 13 contained a point mutation involving the same codon, including 10 with the R147C substitution and 3 with an R147S substitution (102630.0012). Functional analysis in transfected C2C12 myoblast cells suggested a trend towards increased Hedgehog (see 600726) pathway signaling. The authors hypothesized that Becker nevus syndrome may reflect a mutation earlier in development, affecting multiple cell lineages, compared with isolated Becker nevus.
In affected skin from a 17-year-old French girl with Becker nevus syndrome, Ramspacher et al. (2022) identified heterozygosity for a postzygotic mutation, the previously reported R147C substitution.
Congenital Smooth Muscle Hamartoma with or without Hemihypertrophy
In fibroblasts cultured from affected skin of a 2-year-old boy with segmental congenital smooth muscle hamartoma and hemihypertrophy (CSMH; 620470), Atzmony et al. (2020) sequenced the ACTB gene and identified a previously reported postzygotic missense mutation, R147S, which was not found in keratinocytes from the same lesion or in patient saliva. The authors analyzed another 12 samples of CSMHs and identified somatic hotspot mutations in the ACTB gene in 8 samples, including the previously reported R147S mutation and recurrent mutations at residue G146: G146A (102630.0013), G146V (102630.0014), G146D (102630.0015), and G146S (102630.0016) The authors suggested that dissimilarities between Becker nevi and CSMHs might be determined by intrauterine environmental factors, mutation lineage or timing, and/or modifier genes.
Thrombocytopenia 8 with Dysmorphic Features and Developmental Delay
In 6 patients from 4 unrelated families with thrombocytopenia-8 with dysmorphic features and developmental delay (THC8; 620475), Latham et al. (2018) identified heterozygous mutations affecting exons 5 and 6 of the ACTB gene (see, e.g,. 102630.0018-102630.0020). The mutations were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Two mutations were inherited from mildly affected parents and 2 occurred de novo. There was 1 missense variant in exon 5 (M313R), 1 in-frame deletion in exon 6, 1 frameshift in exon 6, and 1 frameshift with protein extension in exon 6. The mutations in exon 6 affected the conserved SD1 domain, which is important for interactions with actin-binding proteins (ABPs). Studies of fibroblasts and platelets derived from affected members of 2 families showed decreased ACTB levels compared to controls. Patient-derived fibroblasts were small and demonstrated impaired migration speed, trajectories, and displacement area compared to controls. There was compensatory upregulation of ACTG1 (102560) and ACTA2 (102620) expression, and ACTB filaments bundled into abnormally thick fibers that incorporated ACTA2. Patient fibroblasts also showed increased recruitment of ABPs associated with macrothrombocytopenia phenotypes (see, e.g. ACTN1, 102575). Patient-derived platelets, which were frequently enlarged, showed abnormal microtubule organization patterns at the platelet cortex. Abnormal microtubule organization patterns were also observed in patient megakaryocytes. The findings suggested that the ACTB mutations inhibit the final stages of platelet maturation by perturbing membrane-associated cytoskeletal filaments.
Latham et al. (2018) referred to the report of Nunoi et al. (1999), who described a 15-year-old Japanese girl with THC8 associated with a heterozygous missense mutation in exon 6 of the ACTB gene (E364K; 102630.0017). Studies of patient B cells showed that although the mutant actin was able to polymerize and depolymerize normally, it had decreased binding efficiency to profilin (see PFN1, 176610). The authors postulated a dominant-negative effect. Although dysmorphic features were not noted in the original report of this child, Latham et al. (2018) stated that the phenotype in this patient was consistent with the disorder described by them.
In a 4-year-old Swedish girl with THC8, Sandestig et al. (2018) identified a de novo heterozygous missense mutation in the ACTB gene (L171F; 102630.0021). The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that the mutation affects a domain involved in interactions with actin-binding proteins.
Exclusion Studies
Verloes et al. (2015) screened a cohort of 95 B-cell acute lymphocytic leukemia (ALL) samples and identified no somatic ACTB mutations.
In the twins with dystonia-deafness syndrome-1 (DDS1; 607371) originally described by Gearing et al. (2002), Procaccio et al. (2006) detected a heterozygous arg183-to-trp (R183W) mutation in the ACTB gene. The amino acid substitution was the result of a c.547C-T transition in exon 4. The constellation of malformations exhibited by the patients resembled Opitz syndrome (300000), but no mutations were found in the MID1 gene (300552) and no evidence was found for involvement of genes causing the autosomal form of Opitz syndrome. No mutations in ACTB were identified in the mother and 2 half brothers. Paternal samples were not available for analysis. Riviere et al. (2012) suggested that this report should be interpreted with caution given the absence of replication studies and unavailability of parental DNA.
In a 15-year-old boy, born of consanguineous Hutterite parents, with DDS1, Conboy et al. (2017) identified a de novo heterozygous R183W mutation in the ACTB gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in several public databases, including the Exome Sequencing Project and ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In a 22-year-old woman with DDS1, Skogseid et al. (2018) identified heterozygosity for the c.547C-T transition (c.547C-T, NM_001101.3) in exon 4 of the ACTB gene resulting in an R183W mutation. The mutation, which was identified by whole-exome sequencing and confirmed with Sanger sequencing, was not present in the patient's mother. The father was not available for testing. Functional studies of the variant and studies of patient cells were not performed.
In a 52-year-old Brazilian woman with DDS1, Freitas et al. (2020) identified heterozygosity for the R183W mutation in the ACTB gene. The mutation was identified by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 34-year-old Argentinian woman with DDS1, Zavala et al. (2022) identified heterozygosity for the R183W mutation in the ACTB gene. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient had similarly affected family members, including her deceased mother and a deceased sib, who did not undergo genetic testing. Functional studies of the variant and studies of patient cells were not performed.
Variant Function
Hundt et al. (2014) found that the R183W mutation increased the affinity of ACTB to DNase1 and resulted in slower filament growth, higher ATP hydrolysis, and faster depolymerization compared to wildtype, resulting in impaired formation of long stable filaments. The mutation also impaired the interaction of ACTB with MYH9 (160775). The findings suggested that the mutation induced a closed-state conformation. Hundt et al. (2014) stated that the mutation results in a gain-of-function effect.
In 7 of 10 patients with Baraitser-Winter syndrome-1 (BRWS1; 243310), Riviere et al. (2012) identified a heterozygous G-to-A transition at nucleotide 587 of the ACTB gene, resulting in an arg-to-his substitution at codon 196 (R196H). In 2 patients from whom parental DNA was available the mutation was determined to have occurred de novo. This mutation was not identified in 212 other exomes. Lymphoblastoid cell lines established from patients carrying this mutation had greatly increased F-actin content and multiple, anomalous F-actin-rich, filopodia-like protrusions compared to control cells, resulting in an increased cell perimeter.
One of the patients found by Riviere et al. (2012) to carry the R196H mutation had been described by Fryns and Aftimos (2000) as patient 1 in the original report of Fryns-Aftimos syndrome.
In an individual with Baraitser-Winter syndrome-1 (BRWS1; 243310), Riviere et al. (2012) identified a heterozygous C-to-T transition at nucleotide 586 of the ACTB gene, resulting in an arg-to-cys substitution at codon 196 (R196C). This mutation was not found in 214 other exomes.
In a patient (patient 3) with a severe BRWS1 phenotype, previously reported by Der Kaloustian et al. (2001), Di Donato et al. (2014) identified a c.586C-T transition (c.586C-T, NM_001101.3) in the ACTB gene, resulting in the R196C mutation. They noted that the patient with the R196C mutation reported by Riviere et al. (2012) had a mild form of the disorder. Di Donato et al. (2014) suggested that the more severe phenotype in their patient may be due to an unknown genetic modifier that has an impact on the clinical severity and malformation spectrum.
In a patient with Baraitser-Winter syndrome-1 (BRWS1; 243310), Riviere et al. (2012) identified a de novo mutation, a heterozygous C-to-G transversion at nucleotide 193 of the ACTB gene resulting in a leu-to-val substitution at codon 65 (L65V). This mutation was not identified in 244 other exomes.
In a patient with Baraitser-Winter syndrome-1 (BRWS1; 243310), Riviere et al. (2012) identified a de novo mutation, a heterozygous A-to-G transition at nucleotide 34 of the ACTB gene resulting in an asn-to-asp substitution at codon 12 (N12D). This mutation was not identified in 24 other exomes.
In a 7-year-old girl with atypical Baraitser-Winter syndrome-1 (243310), who had microcephaly, intellectual disability, and facial dysmorphism but no lissencephaly or seizures, Johnston et al. (2013) identified heterozygosity for a de novo c.349G-A transition in the ACTB gene, resulting in a glu117-to-lys (E117K) substitution. The mutation was not present in either of her unaffected parents. Patient lymphocytes demonstrated significantly decreased ability to adhere to a fibronectin-coated surface and formed few actin-rich protrusions compared to the parents' lymphocytes. Studies in yeast showed virtually complete loss of normal polarization of the cytoskeleton with the mutant, and mutant cells were almost completely resistant to the depolymerizing agent latrunculin A, suggesting that E117K might result in strengthened actin monomer-monomer interactions and increased filament stability.
In a patient (patient 1) with a severe form of Baraitser-Winter syndrome-1 (BRWS1; 243310), who was previously diagnosed with Fryns-Aftimos syndrome, Di Donato et al. (2014) identified a c.359C-T transition (c.359C-T, NM_001101.3) in the ACTB gene, resulting in a thr120-to-ile (T120I) substitution. The mutation was not found in the dbSNP or Exome Variant Server databases.
In 2 patients with severe Baraitser-Winter syndrome-1 (BRWS1; 243310), who were previously diagnosed with cerebrofrontofacial syndrome (Guion-Almeida and Richieri-Costa, 1992; Guion-Almeida and Richieri-Costa, 1999), Verloes et al. (2015) identified the T120I mutation. Verloes et al. (2015) suggested that this mutation is associated with a more severe BRWS phenotype.
In a 12-year-old boy (patient XXIV) with Baraitser-Winter syndrome-1 (BRWS1; 243310), Cuvertino et al. (2017) identified a de novo heterozygous 1-bp duplication (c.1097dupG, NM_001101.3) in exon 6 of the ACTB gene, predicted to result in a frameshift (Ser368LeufsTer13). The mutation, which was found by exome sequencing of a cohort of 4,293 trios in which the offspring had a developmental disorder, was predicted to escape nonsense-mediated mRNA decay, and to result in a loss of function and haploinsufficiency of the ACTB gene.
Greve et al. (2022) noted that the mutation results in an altered C-terminal region of ACTB that includes replacement of the last 8 residues and elongation of the molecule by 4 residues. A different mutation in the ACTB gene (102630.0020) results in the same protein alteration. In vitro studies showed that the mutation perturbed the interaction of ACTB with profilin-1 (176610) and impaired actin dynamics.
In a 14-year-old girl (patient XXV) with Baraitser-Winter syndrome-1 (BRWS1; 243310), Cuvertino et al. (2017) identified a de novo heterozygous c.1117A-T transversion (c.1117A-T, NM_001101.3) in exon 6 of the ACTB gene, resulting in a lys373-to-ter (K373X) substitution. The mutation, which was found by exome sequencing of a cohort of 4,293 trios in which the offspring had a developmental disorder, was predicted to escape nonsense-mediated mRNA decay, and to result in loss of function and haploinsufficiency of the ACTB gene.
In an 18-year-old man (patient XXVI) with Baraitser-Winter syndrome-1 (BRWS1; 243310), Cuvertino et al. (2017) identified a de novo heterozygous 1-bp deletion (c.329delT, NM_001101.3) in exon 3 of the ACTB gene, predicted to result in a frameshift and premature termination (Leu110ArgfsTer10). The mutation, which was found by exome sequencing of a cohort of 4,293 trios in which the offspring had a developmental disorder, was predicted to result in a loss of function and haploinsufficiency of the ACTB gene.
Becker Nevus Syndrome and Becker Nevus
In a 13-year-old girl with Becker nevus syndrome (BNS; 604919), Cai et al. (2017) performed exome sequencing of affected and nonaffected skin and identified heterozygosity for a c.439C-T transition, resulting in an arg147-to-cys (R147C) substitution in lesional skin that was absent from adjacent normal skin. The variant, which affects a highly conserved residue, was not found in the COSMIC, ExAC, or EVS databases. Analysis of 22 nonsyndromic Becker nevi (BN) revealed that 13 contained a point mutation involving the same codon, including 10 with the R147C substitution and 3 with an R147S substitution (102630.0012). Functional analysis in transfected C2C12 myoblast cells suggested a trend towards increased Hedgehog (see 600726) pathway signaling. The authors hypothesized that Becker nevus syndrome may reflect a mutation earlier in development, affecting multiple cell lineages, compared with isolated Becker nevus.
Congenital Smooth Muscle Hamartoma
In affected skin from the left lower back of a 1-year-old girl (MOS4) with congenital smooth muscle hamartoma (CSMH; 620470), Atzmony et al. (2020) identified heterozygosity for the previously reported R147C somatic missense mutation in the ACTB gene.
Becker Nevus
In 3 Becker nevi (BN; 604919) specimens, Cai et al. (2017) identified heterozygosity for a c.439C-A transversion, resulting in an arg147-to-ser (R147S) substitution at a highly conserved residue. The variant was not found in the COSMIC, ExAC, or EVS databases. Functional analysis in transfected C2C12 myoblast cells suggested a trend towards increased Hedgehog (see 600726) pathway signaling.
Congenital Smooth Muscle Hamartoma With Hemihypertrophy
In fibroblasts cultured from affected skin of a 2-year-old boy (MOS1) who had congenital smooth muscle hamartoma with hemihypertrophy of the right upper limb and back (CSMH; 620470), Atzmony et al. (2020) identified heterozygosity for a somatic R147S mutation in the ACTB gene. The variant was not found in keratinocytes from the same lesion or in patient saliva.
In affected skin from the back of a 5-month-old boy (MOS7) and an 8-month-old boy (MOS13) with congenital smooth muscle hamartoma (CSMH; 620470), Atzmony et al. (2020) identified heterozygosity for a somatic c.437G-C transversion at a mutation hotspot in the ACTB gene, resulting in a gly146-to-ala (G146A) substitution.
In affected skin from the left back of a 2-year-old boy (MOS8) with congenital smooth muscle hamartoma (CSMH; 620470), Atzmony et al. (2020) identified heterozygosity for a somatic c.437G-T transversion at a mutation hotspot in the ACTB gene, resulting in a gly146-to-val (G146V) substitution.
In affected skin from the right upper arm of a 1-year-old boy (MOS9) with congenital smooth muscle hamartoma (CSMH; 620470), Atzmony et al. (2020) identified heterozygosity for a somatic c.437G-A transition at a mutation hotspot in the ACTB gene, resulting in a gly146-to-asp (G146D) substitution.
In affected skin from the right thigh of a 1-year-old girl (MOS10) with congenital smooth muscle hamartoma (CSMH; 620470), Atzmony et al. (2020) identified heterozygosity for a somatic c.436G-A transition at a mutation hotspot in the ACTB gene, resulting in a gly146-to-ser (G146S) substitution.
In a 15-year-old Japanese girl with thrombocytopenia-8 with dysmorphic features and developmental delay (THC8; 620475), Nunoi et al. (1999) identified a heterozygous c.1174G-A transition in exon 6 of the ACTB gene, resulting in a glu364-to-lys (E364K) substitution at a conserved residue in a domain important for binding to actin-regulatory molecules. Studies of patient B cells showed that although the mutant actin was able to polymerize and depolymerize normally, it had decreased binding efficiency to profilin (see PFN1, 176610). The authors postulated a dominant-negative effect. In addition to thrombocytopenia, the patient had recurrent infections associated with neutrophil dysfunction (impaired chemotaxis and superoxide generating ability), leukopenia, developmental delay with impaired intellectual development, skin photosensitivity, and short stature. She died of sepsis at 15 years of age. Although dysmorphic features were not noted in the original report of this child, Latham et al. (2018) stated that the phenotype in this patient was consistent with THC8. Latham et al. (2018) referred to this mutation as c.1090G-A (c.1090G-A, NM_001101.3).
Variant Function
Hundt et al. (2014) found that the E364K mutation increased the affinity of ACTB to DNase1 and reduced the exchange of nucleotides. Their studies indicated that mutation caused only minor effects on profilin affinity. Molecular modeling suggested that E364K acts as an allosteric trigger leading to preferred formation of ACTB in the closed state. Hundt et al. (2014) stated that the mutation results in a gain-of-function effect.
In a 5.5-year-old boy (P3) and his 31-year-old mother (P4) (family B) of central European ancestry with thrombocytopenia-8 with dysmorphic features and developmental delay (THC8; 620475), Latham et al. (2018) identified a heterozygous 17-bp deletion (c.992_1008del, NM_001101.3) in exon 6 (the last exon) of the ACTB gene, resulting in a frameshift and premature termination (Ala331ValfsTer27) in the SD1 domain, which is important for interactions with actin-binding proteins (ABPs). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation did not result in nonsense-mediated mRNA decay and a C-terminal frameshift peptide was detected, but overall ACTB protein levels were decreased in patient fibroblasts. Patient-derived fibroblasts were smaller than controls and showed decreased migration speed, trajectories, and displacement area compared to controls. There was compensatory upregulation of ACTG1 (102560) and ACTA2 (102620) expression, and ACTB filaments bundled into abnormally thick fibers that incorporated ACTA2. Patient fibroblasts also showed increased recruitment of ABPs associated with macrothrombocytopenia phenotypes (see, e.g., ACTN1, 102575). Patient-derived platelets, which were frequently enlarged, showed decreased ACTB protein levels and abnormal microtubule organization patterns at the platelet cortex. Similar microtubular disorganization abnormalities were observed in patient megakaryocytes, suggesting that the ACTB mutation inhibits the final stages of platelet maturation by perturbing membrane-associated cytoskeletal filaments.
In a 5-year-old boy (P5, family C) of central European ancestry with thrombocytopenia-8 with dysmorphic features and developmental delay (THC8; 620475), Latham et al. (2018) identified a de novo heterozygous 12-bp in-frame deletion (c.1012_1023del, NM_001101.3) in exon 6 (the last exon) of the ACTB gene, resulting in the deletion of residues 338-341 (Ser338_Ile341del) within the SD1 domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation did not result in nonsense-mediated mRNA decay, but overall ACTB protein levels were decreased in patient fibroblasts. Patient-derived fibroblasts were smaller than controls, formed abnormal clusters, and showed decreased migration speed, trajectories, and displacement area compared to controls. There was compensatory upregulation of ACTG1 (102560) and ACTA2 (102620) expression, and ACTB filaments bundled into abnormally thick fibers that incorporated ACTA2. Patient fibroblasts also showed increased recruitment of ABPs associated with macrothrombocytopenia phenotypes (see, e.g., ACTN1, 102575). Patient-derived platelets, which were frequently enlarged, showed decreased ACTB protein levels and abnormal microtubule organization patterns at the platelet cortex. Similar microtubular disorganization abnormalities were observed in patient megakaryocytes, suggesting that the ACTB mutation inhibits the final stages of platelet maturation by perturbing membrane-associated cytoskeletal filaments.
In a 5.5-year-old girl of Western European origin (P6) with thrombocytopenia-8 with dysmorphic features and developmental delay (THC8; 620475), Latham et al. (2018) identified a de novo heterozygous 1-bp duplication (c.1101dup, NM_001101.3) in exon 6 of the ACTB gene, resulting in the substitution of 8 amino acids and addition of 4 residues at the C-terminus (Ser368LeufsTer13). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. The authors noted that a different mutation in the ACTB gene (102630.0008) results in the same protein alteration.
Variant Function
Greve et al. (2022) demonstrated that the mutation perturbed the interaction of ACTB with profilin-1 (176610) and impaired actin dynamics.
In a 4-year-old Swedish girl with thrombocytopenia-8 with dysmorphic features and developmental delay (THC8; 620475), Sandestig et al. (2018) identified a de novo heterozygous c.511C-T transition (c.511C-T, NM_001101.3) in the ACTB gene, resulting in a leu171-to-phe (L171F) substitution in the W-loop of the protein (SD3 domain). The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that the mutation affects a domain involved in interactions with actin-binding proteins.
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