Alternative titles; symbols
HGNC Approved Gene Symbol: ACTC1
Cytogenetic location: 15q14 Genomic coordinates (GRCh38) : 15:34,790,230-34,795,549 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q14 | Atrial septal defect 5 | 612794 | Autosomal dominant | 3 |
| Cardiomyopathy, dilated, 1R | 613424 | Autosomal dominant | 3 | |
| Cardiomyopathy, hypertrophic, 11 | 612098 | Autosomal dominant | 3 | |
| Left ventricular noncompaction 4 | 613424 | Autosomal dominant | 3 |
ACTC1 is the major component of cardiac sarcomeric thin filaments and is essential for cardiac muscle contraction (summary by Matsson et al., 2008).
Because actin is a highly conserved protein, Engel et al. (1981) could use cloned actin genes from Drosophila and from chicken to isolate 12 actin gene fragments from a human DNA library. Restriction endonuclease studies of each indicated that they are not allelic and are from nonoverlapping regions of the genome. In all, 25 to 30 EcoRI fragments homologous to actin genes were found in the human genome and no restriction site polymorphism was found indicating evolutionary conservatism.
Humphries et al. (1981) used probes from the mouse to detect actin genes in human DNA and concluded that there are about 20 actin genes in the human genome. Three lines of evidence supported this number: the rate of hybridization of the mouse probe with human DNA; the fact that the probe hybridizes to 17-20 bands in Southern blots of restriction enzyme digests of total human DNA; restriction enzyme mapping of individual human actin genes indicating at least 9 different genes, judged on probability grounds to have been picked from a pool of at least 20.
Hamada et al. (1982) isolated and characterized the human cardiac actin gene. The cardiac and skeletal actin genes showed close similarity, suggesting a relatively recent derivation from a common ancestral gene. Nucleotide sequences of all exon/intron boundaries agreed with the GT/AG rule (GT at the 5-prime and AG at the 3-prime termini of each intron). Gunning et al. (1984) noted that the cardiac actin gene and the skeletal actin gene (102610) on chromosome 1 are coexpressed in both skeletal and heart muscle.
Using a cDNA fragment from an exon of the human cardiac actin gene in somatic hybrid cell studies, Shows et al. (1984) showed that the gene is coded by the segment 15q11-qter. Crosby et al. (1989) showed that in the mouse the cardiac actin gene (Actc-1) is not on chromosome 17 as previously reported (Czosnek et al., 1983) but is located on chromosome 2. It is closely linked to beta-2-microglobulin as indicated by mapping studies using restriction fragment variants in recombinant inbred strains. Using a highly polymorphic CA repeat microsatellite within intron 4 of the ACTC gene, Kramer et al. (1992) did family linkage studies with multiple markers on 15q, thus permitting the gene to be placed on the chromosome linkage map. They demonstrated that it lies about 0.06 cM proximal to D15S49, which is about 0.05 cM proximal to D15S25, which in turn is about 0.07 cM proximal to D15S1; D15S1 is tightly linked to the Marfan syndrome and to fibrillin. Thus ACTC may be about 0.18 cM proximal to the fibrillin locus and no more distal than 15q21.1.
By fluorescence in situ hybridization, Ueyama et al. (1995) assigned the ACTC1 gene to chromosome 15q14.
Actin has been identified in many kinds of cells including muscle, where it is a major constituent of the thin filament, and platelets. Muscle actins from sources as diverse as rabbits and fish are very similar in amino acid sequence. Elzinga et al. (1976) examined whether actin in different tissues of the same organism are products of the same gene. They found that human platelet and human cardiac actins differ by one amino acid, viz., threonine and valine, respectively, at position 129. Thus they must be determined by different genes. Actins can be separated by isoelectric focusing into 3 main groups which show more than 90% homology of amino acid sequence. Firtel (1981) referred to the actin of smooth muscle, the most acidic form, as alpha type and the 2 cytoplasmic forms as beta and gamma. Beta and gamma actins are involved in the cytoskeleton and in internal cell mobility phenomena.
The actins constitute multiple gene families. There is only a 4% amino acid difference in the actins of Physarum and mammals. In mammals, 4 different muscle actins have been sequenced: from fast muscle, heart, aorta, and stomach. These vary only by 4 to 6 amino acids from each other, and by about 25 amino acids from the beta and gamma actins. Thus, from the protein data, at least 6 actin genes would be expected in mammals. Recombinant DNA probes for both actin and myosin of the mouse have been made (Weydert et al., 1981).
Buckingham et al. (1986) provided a summary of the actin and myosin multigene families in mouse and man. Certain inbred mouse lines, e.g., BALB/c, have a mutant cardiac actin locus (Garner et al., 1986). The first 3 coding exons and promoter region of the gene are present as a duplication immediately upstream from the cardiac actin gene. The upstream promoter is active, and partial gene transcripts are generated which are correctly spliced for the first 3 coding exons but which terminate at cryptic sites in the region between the duplication and the gene. Transcriptional activity at the upstream promoter interferes with the downstream promoter of the bona fide cardiac actin gene, leading to a 5- to 6-fold reduction in cardiac actin mRNA in the hearts of BALB/c mice. In this situation there is an accumulation of skeletal actin gene transcripts in the adult hearts of these mice, which partially compensates for the reduction in cardiac actin transcripts. BALB/c mice have a normal life span and their hearts do not undergo hypertrophy. Apparently, cardiac and skeletal actins, which differ only by 4 out of 375 amino acids, are to some extent interchangeable. Schwartz et al. (1986) found that under conditions of aortic stenosis leading to cardiac overload and cardiac hypertrophy, skeletal actin gene transcripts are found in adult rodent hearts in addition to the cardiac actin gene products normally present.
Matsson et al. (2008) performed morpholino knockdown of the Actc1 gene in chick embryos and found significant association with delayed looping and reduced atrial septa, supporting a developmental role for the protein.
Fintha et al. (2013) showed that overexpression of mouse Scai (619222) prevented alpha smooth muscle actin (Sma) promoter activation and protein expression induced by Tgf-beta-1 (190180) in mouse LLC-PK1 cells. Coexpression of Scai inhibited the stimulatory effects of Mrtfa (606078), Mrtfb (609463), and the constitutive active forms of Rhoa (165390), Rac1 (602048), and Cdc42 (116952) on the Sma promoter. These inhibitory effects of Scai were dependent on CArG boxes in the Sma promoter. Immunohistochemical analysis revealed reduced SCAI expression during fibrosis in human kidney. Similarly, Scai expression was significantly lost in kidneys of diabetic rats and mice with unilateral ureteral obstruction, resulting in robust expression of Sma.
Litt and Luty (1989) used PCR to amplify a microsatellite hypervariable repeat in the human cardiac actin gene. They detected 12 different allelic fragments in 37 unrelated individuals, of whom 32 were heterozygous.
(Weber and May (1989) also found that (GT)n repeats within human loci are highly polymorphic.) In vertebrates, 6 actin isoforms are known: 4 muscle types (skeletal, cardiac, and 2 smooth muscle types) and 2 nonmuscle types (cytoplasmic actins).
Dilated Cardiomyopathy 1R
To test the hypothesis that actin dysfunction leads to heart failure, Olson et al. (1998) examined patients with hereditary idiopathic dilated cardiomyopathy (see 115200) for mutations in the cardiac ACTC gene. Missense mutations in ACTC (102540.0001 and 102540.0002) that cosegregated with a form of dilated cardiomyopathy, here designated CMD1R (613424), were identified in 2 unrelated families, respectively. Both mutations affected universally conserved amino acids in domains of actin that attached to Z bands and intercalated discs. Coupled with previous data showing that dystrophin mutations also cause dilated cardiomyopathy, these results raised the possibility that defective transmission of force in cardiac myocytes is a mechanism underlying heart failure.
To determine how frequently mutations in the ACTC gene are responsible for dilated cardiomyopathy, Takai et al. (1999) studied 136 Japanese cases of this disorder. Although several polymorphisms were found, no disease-causing changes were identified, leading Takai et al. (1999) to conclude that mutation in the ACTC gene is a rare cause of dilated cardiomyopathy, at least in Japanese patients.
Mayosi et al. (1999) studied 57 South African patients with dilated cardiomyopathy, 56% of whom were of black African origin. No mutation predicted to produce an alteration in protein was identified in either the skeletal or cardiac actin genes in any patient.
Hypertrophic Cardiomyopathy 11
In a large 3-generation family with hypertrophic cardiomyopathy (CMH11; 612098), Mogensen et al. (1999) identified heterozygosity for a missense mutation in the ACTC1 gene (A295S; 102540.0003) that was located near 2 missense mutations previously identified as causing an inherited form of dilated cardiomyopathy (CMD1R). The authors stated that ACTC1 was the first sarcomeric gene described in which mutations are responsible for 2 different cardiomyopathies, and hypothesized that ACTC1 mutations affecting sarcomere contraction lead to HCM and that mutations affecting force transmission from the sarcomere to the surrounding syncytium lead to dilated cardiomyopathy.
Olson et al. (2000) screened the ACTC1 gene in 368 unrelated patients with sporadic or familial CMH and identified 3 different heterozygous mutations in 2 sporadic patients with apical CMH (102540.0007 and 102540.0008, respectively) and in a 4-generation family segregating autosomal dominant CMH (E101K; 102540.0009). None of the mutations was detected in 150 unrelated controls, and each involved a highly conserved residue in ACTC1. The authors noted that these and previously identified CMH-related ACTC1 mutations are likely to affect actin-myosin interaction and force generation; in contrast, CMD-related ACTC1 mutations (e.g., R312H and E361G) are not located in domains interacting with the myosin head, but rather occur in a region of the actin monomer that forms the immobilized end of the actin filament. Olson et al. (2000) concluded that mutations in ACTC1 can cause either CMH or CMD, depending on the functional domain of actin that is affected.
In affected members of 2 families segregating autosomal dominant apical CMH over 3 generations, Arad et al. (2005) identified heterozygosity for the E101K mutation in the ACTC1 gene.
Monserrat et al. (2007) screened 247 probands with CMH, CMD, or left ventricular noncompaction (see LVNC4, 613424) for the E101K mutation, and identified the mutation in 4 probands with CMH, 2 of whom were previously studied by Arad et al. (2005), and in 1 proband with LVNC. Of 46 family members with CMH, 23 fulfilled criteria for LVNC, 22 were diagnosed with apical CMH, and 3 had been diagnosed with restrictive cardiomyopathy. Septal defects were identified in 9 mutation carriers from 4 families (8 atrial defects and 1 ventricular), and were absent in relatives without the mutation. Monserrat et al. (2007) concluded that LVNC and CMH may appear as overlapping entities, and that E101K should be considered in the genetic diagnosis of LVNC, apical CMH, and septal defects.
In 2 unrelated children with idiopathic cardiac hypertrophy and presumed sporadic cardiomyopathy, Morita et al. (2008) identified 2 different missense mutations in the ACTC1 gene (see, e.g., 102540.0004); 1 of the children also carried a missense mutation in the MYH7 gene (160760), which is known to cause CMH1 (192600). The parents were not studied.
Left Ventricular Noncompaction 4
Klaassen et al. (2008) analyzed 6 sarcomere protein genes in 63 unrelated adult probands with left ventricular noncompaction (see LVNC4; 613424) and no other congenital heart anomalies and identified the E101K mutation in the ACTC1 gene in 2 probands.
Atrial Septal Defect 5
Matsson et al. (2008) analyzed the ACTC1 gene in 2 large Swedish families segregating autosomal dominant secundum atrial septal defect (ASD5; 612794) and identified heterozygosity for a mutation (M123V; 102540.0005) in the 20 available affected individuals. The authors studied 408 additional individuals referred for sporadic congenital heart disease and identified a 17-bp deletion (102540.0006) in the ACTC1 gene in a 10-year-old girl with secundum ASD.
In a 36-year-old mother and 2 daughters, aged 5 and 2 years, of German ancestry who had dilated cardiomyopathy (CMD1R; 613424), Olson et al. (1998) found a G-to-A substitution in codon 312 in exon 5 of the ACTC gene, resulting in an arg312-to-his (R312H) amino acid substitution. A 15-year-old son likewise had inherited the mutation but had not developed dilated cardiomyopathy.
In a family of Swedish Norwegian ancestry, Olson et al. (1998) found that a father and son, aged 41 and 14 years, respectively, with dilated cardiomyopathy-1R (CMD1R; 613424) carried a GAG (glu)-to-GGG (gly) mutation in codon 361 in exon 6 of the ACTC gene. In addition, a 34-year-old woman with a dilated heart and a 9-year-old with borderline heart size also had inherited the mutation.
In a 3-generation family with autosomal dominant hypertrophic cardiomyopathy (CMH11; 612098), Mogensen et al. (1999) identified a 253G-T transversion in exon 5 of the ACTC gene resulting in an ala295-to-ser substitution. The ala at position 295 is conserved in 19 different species. The expression of the actin mutation in this family gave the impression of a highly penetrant disease with diverse phenotypes and variable age of onset. Only 1 individual of 13 family members carrying the mutant allele was nonpenetrant, and morbidity was low, as only 3 of the 13 carrying the mutant allele had symptoms of the disease.
In a child with idiopathic cardiac hypertrophy and presumed sporadic cardiomyopathy (CMH11; 612098) who was negative for mutation in 9 of the known CMH genes, Morita et al. (2008) identified a heterozygous C-to-T transition in the ACTC1 gene resulting in a his90-to-tyr (H90Y) substitution. The parents were not studied. The mutation was not found in unrelated individuals matched by ancestral origin or in more than 1,000 control chromosomes.
In 20 affected individuals from 2 Swedish families segregating autosomal dominant atrial septal defect (ASD5; 612794), Matsson et al. (2008) identified heterozygosity for a 373A-G transition in exon 2 of the ACTC1 gene, predicted to result in a met123-to-val (M123V) substitution. Functional analysis of the M123V-mutant protein showed a reduced affinity for myosin, but retention of actin filament polymerization and actomyosin motor properties. The mutation was not found in 580 control samples.
In a 10-year-old girl with a secundum atrial septal defect (ASD5; 612794), Matsson et al. (2008) identified heterozygosity for a 17-bp deletion beginning at nucleotide 251 in exon 2 of the ACTC1 gene, predicted to result in a severely truncated protein of 86 amino acids in length. The mutation was also identified in her clinically unaffected 43-year-old father, who was found to have an abnormal echocardiogram with a posteriorly deviated interventricular septum, believed to be associated with a spontaneously closed perimembranous ventricular septal defect, causing aortic valve regurgitation. The deletion was not found in 580 control samples.
In a 21-year-old man with hypertrophic cardiomyopathy (CMH11; 612098), Olson et al. (2000) identified heterozygosity for a G-C transversion in exon 6 of the ACTC1 gene, resulting in an ala331-to-pro (A331P) substitution at a highly conserved residue. The patient presented at 8 years of age with 2 near-syncopal episodes and was diagnosed with idiopathic CMH. At 10 years of age, he was resuscitated from ventricular fibrillation that occurred while running, and a defibrillator was placed. Cardiac evaluation revealed hypertrophy of the septum and left ventricular apex. His unaffected parents did not carry the mutation, nor was it found in 150 unrelated controls.
In a 12-year-old boy with hypertrophic cardiomyopathy-11 (CMH11; 612098), Olson et al. (2000) identified heterozygosity for a C-G transversion in exon 2 of the ACTC1 gene, resulting in a pro164-to-ala (P164A) substitution at a highly conserved residue. The patient was diagnosed with CMH at 17 months of age due to syncopal episodes. He later had occasional episodes of chest pain, dyspnea, and near-syncope, and underwent insertion of a pacemaker. Cardiac evaluation revealed hypertrophy of the septum and left ventricular apex. His unaffected parents did not carry the mutation, nor was it found in 150 unrelated controls.
Using a new numbering system, Arad et al. (2005) designated this mutation GLU101LYS (E101K).
In 7 affected members of a 4-generation family segregating autosomal dominant hypertrophic cardiomyopathy (CMH11; 612098), Olson et al. (2000) identified heterozygosity for a G-A transition in exon 2 of the ACTC1 gene, resulting in a glu99-to-lys (GLU99LYS) substitution at a highly conserved residue. Apical left ventricular hypertrophy was present in 5 cases and a trabeculated apex in 2 cases; 2 individuals also had marked hypertrophy of the interventricular septum without left ventricular outflow obstruction, and 1 had an atrial septal defect.
In affected members of 2 families segregating autosomal dominant apical CMH over 3 generations, Arad et al. (2005) identified heterozygosity for the E101K mutation in the ACTC1 gene. A shared haplotype was also identified, providing odds greater than 100:1 that E101K represents a founding mutation in the 2 families; however, haplotype data indicated that E101K arose independently in the family reported by Olson et al. (2000). Of 18 mutation-positive individuals studied by Arad et al. (2005), 2 individuals, ages 10 and 29 years, had no clinical evidence of cardiomyopathy. Isolated apical hypertrophy was found in 5 individuals; 11 others also had mild thickening of the basal segments and/or involvement of the midventricular segment, and 2 also had trabeculation of the apex. Right ventricular endomyocardial biopsy in 1 patient revealed myocyte hypertrophy and disarray with extensive replacement fibrosis that was more marked than that typically seen in CMH associated with other morphologic patterns of hypertrophy.
Monserrat et al. (2007) screened 247 probands with CMH, dilated cardiomyopathy (CMD), or left ventricular noncompaction (see LVNC4, 613424) for the E101K mutation, and identified the mutation in 4 probands with CMH and 1 with LVNC. The 5 mutation-positive families, 2 of which were previously studied by Arad et al. (2005), were all from the same local area in Galicia, Spain, and shared the same 88-bp allele of the intragenic ACTC1 microsatellite marker that cosegregated with disease in the families, suggesting a likely founder effect. Of 46 family members with CMH, 23 fulfilled criteria for LVNC, 22 were diagnosed with apical CMH, and 3 had been diagnosed with restrictive cardiomyopathy. Septal defects were identified in 9 mutation carriers from 4 families (8 atrial defects and 1 ventricular), and were absent in relatives without the mutation. The E101K mutation was not found in 48 unaffected family members. Monserrat et al. (2007) concluded that LVNC and CMH may appear as overlapping entities, and that E101K should be considered in the genetic diagnosis of LVNC, apical CMH, and septal defects.
In a 15-year-old girl and an unrelated 38-year-old woman with LVNC, Klaassen et al. (2008) identified heterozygosity for the E101K mutation in the ACTC1 gene. Both had inherited the mutation from their affected fathers; haplotype analysis excluded a common ancestor. All 4 patients had noncompaction of the apex and midventricular wall and no other congenital cardiac anomalies.
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