Alternative titles; symbols
HGNC Approved Gene Symbol: ACTG1
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:81,509,971-81,512,799 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Baraitser-Winter syndrome 2 | 614583 | Autosomal dominant | 3 |
| Deafness, autosomal dominant 20/26 | 604717 | Autosomal dominant | 3 |
Actins are a family of highly conserved cytoskeletal proteins that play fundamental roles in nearly all aspects of eukaryotic cell biology. The ability of a cell to divide, move, endocytose, generate contractile force, and maintain shape is reliant upon functional actin-based structures. Actin isoforms are grouped according to expression patterns: muscle actins predominate in striated and smooth muscle (e.g., ACTA1, 102610, and ACTA2, 102620, respectively), whereas the 2 cytoplasmic nonmuscle actins, gamma-actin (ACTG1) and beta-actin (ACTB; 102630), are found in all cells (Sonnemann et al., 2006).
Using chick beta-actin cDNA as probe, Gunning et al. (1983) cloned beta-actin and gamma-actin from a fibroblast cDNA library. They noted that the N-terminal methionine is posttranslationally removed from the mature beta-actin and gamma-actin proteins.
Erba et al. (1986) presented the complete sequence of gamma-actin mRNA. They noted that gamma- and beta-actin differ by only 4 amino acids at their conserved N-terminal ends.
By screening a promyelocytic leukemia cell line cDNA library with chicken beta-actin, Chou et al. (1987) cloned human gamma-actin. The deduced protein contains 375 amino acids. Northern blot analysis of human fetal tissues detected highest expression of a 2.35-kb transcript in brain and kidney, with weaker expression in liver and trophoblasts. High expression was also detected in a human hepatoma cell line. Expression of gamma-actin increased during macrophage differentiation in a neuroblastoma cell line.
By Northern blot analysis of mouse tissues, Erba et al. (1988) detected high gamma-actin expression in lung, kidney, and testis, moderate expression in brain, low expression in stomach, and very low expression in liver, heart, and muscle.
Loisel et al. (1999) used pure components of the actin cytoskeleton to reconstitute sustained movement in Listeria and Shigella in vitro. Actin-based propulsion was driven by the free energy released by ATP hydrolysis linked to actin polymerization and did not require myosin (see 601478). In addition to actin and activated Arp2/3 complex (see 604221), actin depolymerizing factor and capping protein (see 601571) were also required for motility as they maintained a high steady-state level of G-actin, (monomeric, or globular, actin) which controls the rate of unidirectional growth of actin filaments at the surface of the bacterium. The movement was more effective when profilin (see 176590), alpha-actinin (see 102575), and, in the case of Listeria, VASP (601703) were also included.
Tzima et al. (2000) showed that annexin V (ANXA5; 131230) bound filamentous actin (F-actin) and gamma-actin, but not beta-actin, in activated human platelets.
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 G-actin inhibited both basal and stimulated PLD1 activity, whereas 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.
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.
Crystal Structure
Otterbein et al. (2001) determined the crystal structure at 1.54-angstrom resolution of actin in the ADP state modified to block polymerization. Compared with ATP-actin structures from complexes with deoxyribonuclease I (125505), profilin, and gelsolin (137350), monomeric ADP-actin is characterized by a marked conformational change in subdomain 2.
Erba et al. (1988) determined that the ACTG1 gene contains 6 exons. The 5-prime flanking region contains TATA and CCAAT boxes, an SRF (600589)-binding site, and 5 SP1 (189906)-binding sites. The ACTB gene has a structure similar to that of ACTG1, suggesting that ACTB and ACTG1 arose by duplication of a common ancestor.
Erba et al. (1988) demonstrated that the human gamma-actin gene is located on chromosome 17 by Southern analysis of DNA from human-mouse somatic cell hybrids. Hybridization of the probe to the genome of a human-mouse cell hybrid containing a 17;9 translocation indicated that the gene is located in the region 17p11-qter.
Ueyama et al. (1996) mapped the ACTG1 gene to 17q25 and 3 ACTG pseudogenes to other chromosomes.
DFNA20/26
Zhu et al. (2003) identified 4 families segregating an autosomal dominant progressive sensorineural hearing loss, designated DFNA20 or DFNA26 (see 604717), that had been linked to 17q25.3. They narrowed the critical interval containing the causative gene to approximately 2 million bp between markers D17S914 and D17S668, and sequenced cochlear-expressed genes within this interval in affected family members. In all 4 families, they identified missense mutations in highly conserved actin domains of the ACTG1 gene (102560.0001-102560.0004). Much of the specialized ultrastructural organization of the cells in the cochlea was based on the actin cytoskeleton. Zhu et al. (2003) noted that many of the mutations known to cause either syndromic or nonsyndromic deafness occur in genes that interact with actin. They stated that this was the first description of a mutation in cytoskeletal, or nonmuscle, actin.
In 19 affected individuals of a large Norwegian family reported by Teig (1968), Rendtorff et al. (2006) identified a heterozygous mutation in the ACTG1 gene (102560.0006). No mutations in the ACTG1 gene were identified in 19 additional Norwegian and Danish families with autosomal dominant hearing loss, suggesting that it is not a frequent cause in this population.
Baraitser-Winter Syndrome 2
Riviere et al. (2012) reported 8 patients with Baraitser-Winter syndrome (BRWS2; 614582) with heterozygous missense mutations in the ACTG1 gene. Seven of 8 of these patients were proven to have de novo mutations. One mutation was recurrent in 3 patients, a ser-to-phe substitution at codon 155 (S155F; 102560.0009). All the others had novel missense mutations (102560.0010-102560.0014). Congenital or later-onset progressive hearing loss is a common feature of Baraitser-Winter syndrome, and Riviere et al. (2012) suggested that Baraitser-Winter syndrome represents the severe end of a spectrum of cytoplasmic actin-associated phenotypes that begins with Baraitser-Winter syndrome and extends to nonsyndromic hearing loss.
To study the role of ACTG1 in skeletal muscle development and avoid the near-certain embryonic lethality of conventional Actg1 knockout, Sonnemann et al. (2006) conditionally ablated Actg1 expression in mouse skeletal muscle. Although muscle development proceeded normally, Actg1-knockout mice presented with overt muscle weakness accompanied by a progressive pattern of muscle fiber necrosis and regeneration. The phenotype resembled human centronuclear myopathies, which are typically associated with perturbations in enzyme activity, muscle development, or excitation-contraction coupling.
In 17 affected members of a family segregating autosomal dominant progressive sensorineural hearing loss (604717), Zhu et al. (2003) identified a 340C-T transition in exon 3 of the processed ACTG1 mRNA, resulting in a thr89-to-ile (T89I) substitution in subdomain 1. The mutation is in an alpha helix that is thought to participate in the binding of fimbrin (PLS3; 300131), a bundling protein. This amino acid is perfectly conserved in cytoplasmic actin, in species ranging from nematodes to mammals. The mutation was not identified in 220 control chromosomes.
In 8 affected members of a family segregating autosomal dominant progressive sensorineural hearing loss (604717), Zhu et al. (2003) identified a lys118-to-met (K118M) mutation in exon 3 of the ACTG1 gene. The substitution occurs in subdomain 1 of the protein near the fimbrin (PLS3; 300131)-binding domain. The family had been reported by Yang and Smith (2000).
In 8 affected members of a family segregating autosomal dominant progressive sensorineural hearing loss (604717), Zhu et al. (2003) identified a pro332-to-ala (P332A) missense mutation in the ACTG1 gene. The family had been reported by Yang and Smith (2000). P332A is in a 3-amino acid loop in subdomain 3 of the protein; this loop may be part of the primary contact site for myosin.
In 11 affected members of a family segregating autosomal dominant progressive sensorineural hearing loss (604717) reported by DeWan et al. (2003), Zhu et al. (2003) identified a pro264-to-leu (P264L) missense mutation in the gamma-actin gene. P264L is in a proposed hydrophobic plug for interstrand interactions in subdomain 4 of the protein, near the actin self-assembly site. Affected members had an early age at onset and rapid progression of hearing loss.
In a Dutch family with autosomal dominant deafness linked to the DFNA20 region (604717), Van Wijk et al. (2003) found that affected members had an 833C-T transition in exon 5 of the ACTG1 gene, resulting in a thr278-to-ile (T278I) substitution. The mutation was identified in helix 9 of the modeled protein structure and was predicted to have a small but significant effect on the gamma-1 actin structure owing to its close proximity to a methionine residue at position 313 in helix 11. The authors suggested that the mutation would interfere with actin polymerization.
In 19 affected members of a large Norwegian family with autosomal dominant DFNA20 (604717), Rendtorff et al. (2006) identified a heterozygous 1109T-C transition in exon 6 of the ACTG1 gene, resulting in a val370-to-ala (V370A) substitution in a highly conserved region. Functional expression studies in yeast showed that the mutant protein suppressed growth; computer modeling suggested that the V370A substitution impaired hydrophobic interactions and destabilized the position of the C-terminal tail of the protein. The family had originally been reported by Teig (1968).
In a Spanish father and daughter with autosomal dominant deafness (604717), Morin et al. (2009) identified heterozygosity for a 354G-C transversion in exon 3 of the ACTG1 gene, resulting in a lys118-to-asn (K118N) substitution in subdomain 1. The mutation was not found in 100 normal unrelated Spanish controls. Both father and daughter showed bilateral, symmetric, progressive sensorineural hearing loss at mid and high frequencies of postlingual onset. The daughter had onset in the third decade, and the father had even later onset. Morin et al. (2009) showed that the K118N mutation had a very mild effect in yeast. In transiently transfected NIH3T3 cells, K118N-mutant actin was normally incorporated into cytoskeleton structures, although cytoplasmic aggregates were also observed indicating an element of abnormality caused by the K118N mutation in vivo. Gene-gun mediated expression of K118N mutant in mouse cochlear hair cells resulted in no gross alteration in cytoskeletal structures or the morphology of stereocilia. Morin et al. (2009) supported the hypothesis that the postlingual and progressive nature of the DFNA20/26 hearing loss may be the result of a progressive deterioration of the hair cell cytoskeleton over time.
In 4 affected members of a Spanish family with autosomal dominant deafness (604717), Morin et al. (2009) identified heterozygosity for a 721G-A transition in exon 4 of the ACTG1 gene, resulting in a glu241-to-lys (E241K) substitution in subdomain 4. The mutation was not found in 100 normal unrelated Spanish controls. The affected members were referred for hearing loss at school age, with the earliest individual referred at age 6 years. All showed postlingual, bilateral, symmetric, progressive sensorineural hearing loss at mid and high frequencies. In yeast, the E241K mutation resulted in a severe phenotype characterized by a highly compromised ability to grow on glycerol as a carbon source, an aberrant multivacuolar pattern, and deposition of thick F-actin bundles randomly in the cell. The latter feature is consistent with the unusual tendency of the E241K mutant to form bundles in vitro, although this propensity to bundle was neutralized by tropomyosin (TPM1; 191010) and the E241K filament bundles were hypersensitive to severing in the presence of cofilin (CFL1; 601442). In transiently transfected NIH3T3 cells, E241K-mutant actin was normally incorporated into cytoskeleton structures, although cytoplasmic aggregates were also observed indicating an element of abnormality caused by the mutations in vivo. Gene-gun mediated expression of the E241K mutant in mouse cochlear hair cells resulted in no gross alteration in cytoskeletal structures or the morphology of stereocilia. Morin et al. (2009) supported the hypothesis that the postlingual and progressive nature of the DFNA20/26 hearing loss may be the result of a progressive deterioration of the hair cell cytoskeleton over time.
In 3 unrelated individuals with Baraitser-Winter syndrome-2 (BRWS2; 614583), Riviere et al. (2012) identified a heterozygous C-to-T transition at nucleotide 464 of the ACTG1 gene, resulting in a ser-to-phe substitution at codon 155 (S155F). This mutation was proven to have occurred de novo in 2 of the 3; in the third, parental DNA was not available. One of these 3 patients, LP98-096, was reported by Baraitser and Winter (1988). This mutation was not identified in 224 control exomes. Riviere et al. (2012) studied lymphoblastoid cell lines from individuals carrying the S155F mutation and demonstrated that these had increased F-actin content and multiple, anomalous F-actin-rich filopodia-like protrusions compared to control cells, resulting in increased cell perimeter. Cell lines also showed increased sensitivity to treatment with latrunculin A.
Riviere et al. (2012) reported a single individual with Baraitser-Winter syndrome-2 (BRWS2; 614583) carrying a de novo heterozygous mutation in ACTG1, a C-to-T transition at nucleotide 359 resulting in a thr-to-ile substitution at codon 120 (T120I). This mutation was not observed in 244 other exomes sequenced.
In an individual with Baraitser-Winter syndrome-2 (BRWS2; 614583), Riviere et al. (2012) identified a heterozygous C-to-T transition at nucleotide 404 of the ACTG1 gene, resulting in an ala-to-val substitution at codon 135 (A135V). This mutation occurred de novo in the patient and was not observed in 192 other exomes sequenced.
In an individual with Baraitser-Winter syndrome-2 (BRWS2; 614583), Riviere et al. (2012) identified a heterozygous C-to-A transversion at nucleotide 608 of the ACTG1 gene, resulting in an thr-to-lys substitution at codon 203 (T203K). This mutation occurred de novo in the patient and was not observed in 203 other exomes sequenced.
In an individual with Baraitser-Winter syndrome-2 (BRWS2; 614583), Riviere et al. (2012) identified a heterozygous C-to-T transition at nucleotide 760 of the ACTG1 gene, resulting in an arg-to-trp substitution at codon 254 (R254W). This mutation occurred de novo in the patient and was not observed in 195 other exomes sequenced.
In an individual with Baraitser-Winter syndrome-2 (BRWS2; 614583), Riviere et al. (2012) identified a heterozygous C-to-T transition at nucleotide 766 of the ACTG1 gene, resulting in an arg-to-trp substitution at codon 256 (R256W). This mutation occurred de novo in the patient and was not observed in 184 other exomes sequenced.
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