Alternative titles; symbols
HGNC Approved Gene Symbol: ACTA1
SNOMEDCT: 1217226000, 702349003;
Cytogenetic location: 1q42.13 Genomic coordinates (GRCh38): 1:229,431,245-229,434,094 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q42.13 | ?Myopathy, scapulohumeroperoneal | 616852 | Autosomal dominant | 3 |
| Congenital myopathy 2A, typical, autosomal dominant | 161800 | Autosomal dominant | 3 | |
| Congenital myopathy 2B, severe infantile, autosomal recessive | 620265 | Autosomal recessive | 3 | |
| Congenital myopathy 2C, severe infantile, autosomal dominant | 620278 | Autosomal dominant | 3 |
The ACTA1 gene encodes skeletal muscle alpha-actin, the principal actin isoform in adult skeletal muscle, which forms the core of the thin filament of the sarcomere where it interacts with a variety of proteins to produce the force for muscle contraction (Laing et al., 2009).
Using chick beta-actin cDNA as probe, Gunning et al. (1983) cloned alpha-actin from a human muscle cDNA library. They also cloned beta-actin (ACTB; 102630) and gamma-actin (ACTG1; 102560) from a fibroblast cDNA library. Sequence analysis of the 5-prime ends revealed that alpha-actin starts with both a methionine and a cysteine not found in the mature protein. They concluded that, since no known actin proteins start with a cysteine, there must be posttranslational removal of cysteine in addition to methionine in alpha-actin synthesis, but not in beta- or gamma-actin synthesis.
Hanauer et al. (1983) cloned alpha-actin from a cDNA library developed from quadriceps muscle mRNA using mouse skeletal alpha-actin cDNA as probe. The sequence is characterized by a high GC content (61.6%). Hanauer et al. (1983) noted conservation of the amino acid sequence between human and rat actins, and a comparison of the coding sequences revealed 61% silent changes.
Taylor et al. (1988) cloned alpha-actin and determined that the primary transcript encodes a 377-amino acid protein, including the first 2 residues, which are absent from the mature protein. They noted that the same 2 codons precede the codon specifying the N-terminal amino acid in the homologous genes of rat, mouse, chicken, Drosophila, and sea urchin.
Taylor et al. (1988) determined that the alpha-actin gene contains 7 exons. There is a large intron in the 5-prime untranslated region that is characteristic of actins and many muscle-specific genes. The promoter contains a TATA box and 3 conserved CArG boxes; Taylor et al. (1988) showed that these were activated by muscle cell differentiation in a rat myogenic cell line. The 3-prime untranslated region contains a GC-rich region as well as a putative poly(A) addition signal.
By use of a cDNA probe in somatic cell hybrids, Hanauer et al. (1984) assigned the gene for the alpha chain of skeletal muscle actin to chromosome 1. Actin sequences were found at high stringency also at 2p23-qter and 3pter-q21. Under conditions of low or medium stringency, actin sequences were demonstrated on the X (p11-p12) and Y chromosomes. The actin genes assigned to the X and Y chromosomes (Heilig et al., 1984; Koenig et al., 1985) appear to be intronless pseudogenes.
Using a cDNA copy of the 3-prime untranslated region of the human skeletal alpha-actin gene, Shows et al. (1984) mapped the gene to 1p12-qter. This gene and that for cardiac alpha-actin (ACTC; 102540) are coexpressed in both human skeletal muscle and heart. Coexpression is not a function of linkage; the loci are on separate chromosomes: 1p21-qter and 15q11-qter, respectively (Gunning et al., 1984). Using a panel of somatic cell hybrids, Alonso et al. (1993) confirmed the localization of the ACTA1 gene on human chromosome 1. Akkari et al. (1994) narrowed the assignment of the ACTA1 gene to 1q42 by fluorescence in situ hybridization. Also by fluorescence in situ hybridization, Ueyama et al. (1995) mapped the gene to 1q42.1.
On the basis of analysis of mouse/hamster somatic cell hybrids segregating mouse chromosomes, Czosnek et al. (1982) concluded that the skeletal actin gene is located on mouse chromosome 3. However, Alonso et al. (1993) found by PCR analysis of a microsatellite in an interspecific backcross that the alpha-actin gene is closely linked to tyrosine aminotransferase and adenine phosphoribosyltransferase on mouse chromosome 8. The Acta1 gene is situated between Tat and Aprt; the human homologs TAT (613018) and APRT (102600) are on human chromosome 16. Abonia et al. (1993) likewise mapped the Acta1 gene to mouse chromosome 8 by segregation of RFLVs in 2 interspecific backcross sets and in 4 recombinant inbred mouse sets.
Actin makes up 10 to 20% of cellular protein and has vital roles in cell integrity, structure, and motility. It is highly conserved throughout evolution. Its function depends on the balance between monomeric (globular) G-actin (42 kD) and (filamentous) F-actin, a linear polymer of G-actin subunits. Among the cytosolic actin-binding proteins, 3 appear to be of primary importance in limiting polymerization: profilin (176590, 176610), thymosin beta-4 (300159), and gelsolin (GSN; 137350). The existence of intracellular actin-binding proteins allows the concentration of G-actin to be maintained substantially above the threshold at which polymerization and the formation of filaments would normally occur. When released into the extracellular space, actin, which otherwise is known to have a pathologic effect, is bound by gelsolin and by the Gc protein (GC; 139200). This is the so-called extracellular actin-scavenger system (Lee and Galbraith, 1992).
Oda et al. (2009) created a model of F-actin using x-ray fiber diffraction intensities obtained from well oriented sols of rabbit skeletal muscle F-actin to 3.3 angstroms in the radial direction and 5.6 angstroms along the equator. The authors showed that the G- to F-actin conformational transition is a simple relative rotation of the 2 major domains by about 20 degrees. As a result of the domain rotation, the actin molecule in the filament is flat. The flat form is essential for the formation of stable, helical F-actin. Oda et al. (2009) concluded that their F-actin structure model provided a basis for understanding actin polymerization as well as its molecular interactions with actin-binding proteins.
Mutations in the ACTA1 gene cause congenital myopathy that varies clinically, ranging from death in infancy to adult survival. Most patients (90%) carry heterozygous mutations, the majority of which occur de novo and encode missense variants that likely act in a dominant-negative manner and cause typical congenital myopathy-2A (CMYP2A; 161800). Most patients with a heterozygous mutation have a typical presentation, but some have severe infantile congenital myopathy-2C (CMYP2C; 620278). Rare families who demonstrate autosomal dominant transmission of the disorder are less severely affected, since affected individuals survive to reproductive age. Patients with biallelic ACTA1 mutations (10%) showing autosomal recessive inheritance (CMYP2B; 620265) have a severe phenotype, often with loss of expression of the ACTA1 protein due to frameshift or nonsense mutations. These likely act as loss-of-function alleles since carrier parents are unaffected (review by Sparrow et al., 2003).
By immunoblot analysis, Ilkovski et al. (2004) showed that muscle from patients with ACTA1 mutations had increased levels of gamma-filamin (FLNC; 102565), myotilin (TTID; 604103), desmin (DES; 125660), and alpha-actinin (ACTN1; 102575), consistent with accumulation of Z line-derived nemaline bodies. Intranuclear aggregates were observed upon transfecting myoblasts with V163L (102610.0004)-null-, V163L (102610.0024)-null-, V163M (102610.0014)-null-, and R183G-null-acting transgene constructs, and modeling showed these residues to be adjacent to the nuclear export signal of actin. Transfection studies further showed significant alterations in the ability of V136L and R183G actin mutants to polymerize and contribute to insoluble acting filaments. In vitro studies suggested that abnormal folding, altered polymerization, and aggregation of mutant actin isoforms may be common properties of NM ACTA1 mutants. A combination of these effects may contribute to the common pathologic hallmarks of NM, namely intranuclear and cytoplasmic rod formation, accumulation of thin filaments, and myofibrillar disorganization.
Laing et al. (2009) provided a review of mutations and polymorphisms in the ACTA1 gene and described 85 novel mutations. Mutations are spread throughout the 6 coding exons, and there are no mutation hotspots. Irrespective of the pathology, ACTA1 mutations usually result in a clinically severe myopathy, with many patients dying in the first years of life. Most mutations are dominant, and most of these are de novo. About 10% mutations are recessive and functionally null.
Congenital Myopathy 2A, Typical, Autosomal Dominant
In 2 unrelated patients (P7 and P10) with autosomal dominant typical congenital myopathy-2A (CMYP2A; 161800), Nowak et al. (1999) identified heterozygous missense mutations in the ACTA1 gene (M132V and G182D). Clinical details were limited, but these patients were classified as having a milder disease; they were alive at 3 and 39 years of age.
In 2 unrelated patients (P3 and P4) with a typical form of CMYP2A, Ilkovski et al. (2001) identified 2 different heterozygous missense mutations in the ACTA1 gene: P3 carried a de novo G286C mutation (102610.0007), whereas P4 carried a heterozygous I136M mutation (102610.0008) that likely occurred de novo since he had no family history of a similar disorder.
In a Japanese boy with CMYP2A who died of cardiomyopathy at age 9.5 years, Gatayama et al. (2013) identified a heterozygous missense mutation in the ACTA1 gene (W358C; 102610.0017). Gatayama et al. (2013) noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations.
In affected members of 2 families with CMYP2A manifest as 'core only' myopathy, Kaindl et al. (2004) identified heterozygous missense mutations in the ACTA1 gene (102610.0009-102610.0010). Patients of both families showed a mild and nonprogressive course of skeletal muscle weakness. The myopathy was accompanied by adult-onset hypertrophic cardiomyopathy and respiratory failure in 1 family. Histologically, cores were detected in the muscle fibers of at least 1 patient in each family, whereas nemaline bodies or rods and actin filament accumulation were absent. Kaindl et al. (2004) concluded that their findings established mutation in the ACTA1 gene as a cause of dominant congenital myopathy with cores and delineated another clinicopathologic phenotype for ACTA1.
In 4 patients from a 3-generation family with autosomal dominant CMYP2A, Hutchinson et al. (2006) identified a heterozygous mutation in the ACTA1 gene (V163M; 102610.0014) that segregated with the disorder.
Sparrow et al. (2003) reported a 42-year-old patient classified as having a 'typical' form of CMYP2A who carried a heterozygous H40Y mutation (see 102610.0026). He had no family history of the disorder. Further clinical details were not provided.
Congenital Myopathy 2C, Severe Infantile, Autosomal Dominant
In 3 patients with severe infantile autosomal dominant congenital myopathy-2C (CMYP2C; 620278) reported by Goebel et al. (1997), Nowak et al. (1999) identified heterozygous missense mutations in the ACTA1 gene (102610.0003; 102610.0004; 102610.0024). The mutations were demonstrated to occur de novo in patients 1 and 2; parental DNA from patient 3 was not available. Nowak et al. (1999) also identified heterozygous, mostly de novo, missense mutations in the ACTA1 gene (see, e.g., 102610.0025 and 102610.0026), in 7 additional patients with severe congenital myopathy. Clinical details were limited, but most of the patients died in infancy. One patient (P10) classified as severe was still alive at 10 years of age. The missense mutations in ACTA1 were distributed throughout all 6 coding exons and some involved known functional domains of actin.
In 3 unrelated patients with severe infantile CMYP2C, Laing et al. (2004) identified 3 different heterozygous missense mutations in the ACTA1 gene (102610.0011-102610.0013). Parental DNA was not available for any of the cases, but there was no family history of myopathy, suggesting that the mutations occurred de novo.
In a male infant (25-1) with severe infantile CMYP2C, Agrawal et al. (2004) identified a heterozygous missense mutation in the ACTA1 gene (D286G; 102610.0025). There was no family history of the disease, and this was an isolated case, likely due to a de novo mutation (parental DNA was not available for study).
In a male infant with severe infantile CMYP2C, Garcia-Angarita et al. (2009) identified heterozygosity for an allele carrying 2 de novo mutations in cis affecting adjacent nucleotides in the ACTA1 gene (E74D and H75Y; 102610.0015). Neither unaffected parent carried either of the mutations.
In a patient with severe infantile CMYP2C, Jain et al. (2012) identified a de novo heterozygous activating mutation in the ACTA1 gene (K328N; 102610.0016).
Congenital Myopathy 2B, Autosomal Recessive
In 2 infant sibs (family 5) with autosomal recessive congenital myopathy-2B (CMYP2B; 620265) leading to death at 5 and 19 days of age, Nowak et al. (1999) identified compound heterozygous missense mutations in the ACTA1 gene (L94P; 102610.0001 and E259V; 102610.0005). Each of the mutations was inherited from an unaffected parent, consistent with autosomal recessive inheritance.
In 5 patients from 3 unrelated families with CMYP2B resulting in death in infancy, Sparrow et al. (2003) identified homozygous or compound heterozygous mutations in the ACTA1 gene (102610.0005; 102610.0019-102610.0021). All patients carried at least 1 nonsense or frameshift mutation. In 1 family, the unaffected parents were heterozygous for the mutation. Functional studies of the variants were not performed, but all were predicted to have a loss-of-function effect. Biallelic ACTA1 mutations were present in only a minority of the large patient cohort studied.
In 7 patients from 6 unrelated consanguineous families with CMYP2B, Nowak et al. (2007) identified homozygous frameshift mutations in the ACTA1 gene (see, e.g., c.541delG, 102610.0022). In cases where DNA was available, the unaffected parents were heterozygous for the mutation. One of the patients had previously been reported by Sparrow et al. (2003). Four families were of Pakistani and Indian British origin, and haplotype analysis was consistent with a founder effect for the c.541delG mutation. Five of the children died of respiratory failure in infancy, whereas 1 was alive at 4.5 years of age and another at 2.5 years of age. Skeletal muscle biopsy from some of the patients showed absence of the ACTA1 protein with increased expression of cardiac alpha-actin (ACTC1; 102540), likely reflecting a compensatory mechanism.
In 2 brothers, born of consanguineous Sri Lankan parents, with CMYP2B, O'Grady et al. (2015) identified a homozygous missense mutation in the ACTA1 gene (V154L; 102610.0023). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous parents were unaffected. Functional studies of the variant were not performed, but it was predicted to be deleterious. Immunostaining and Western blot analysis of patient muscle showed normal levels of skeletal muscle ACTA1 and upregulated expression of cardiac alpha-actin (ACTC1; 102540). O'Grady et al. (2015) noted that previously reported patients with biallelic ACTA1 mutations had functional 'null' variants and made no ACTA1 protein. Survival after birth was attributed to persistence of cardiac ACTC1 in the skeletal muscle of these children.
Scapulohumeroperoneal Myopathy
In affected members of a large family with scapulohumeroperoneal myopathy (SHPM; 616852), Zukosky et al. (2015) identified a heterozygous missense mutation in the ACTA1 gene (E197D; 102610.0018).
Ilkovski et al. (2001) evaluated a new series of 35 patients with nemaline myopathy. They identified 5 unrelated patients with a missense mutation in the ACTA1 gene (see, e.g., 102610.0002; 102610.0006-102610.0008), which suggested that mutations in this gene account for the disease in approximately 15% of patients. All 5 mutations were novel, de novo dominant mutations. One proband subsequently had 2 affected children, a result consistent with autosomal dominant transmission. The 7 patients exhibited marked clinical variability, ranging from severe congenital weakness, with death from respiratory failure during the first year of life, to a mild childhood-onset myopathy with survival into adulthood. There was marked variation in both age at onset and clinical severity in the 3 affected members of 1 family. Pathologic features shared by the patients included abnormal fiber-type differentiation, glycogen accumulation, myofibrillar disruption, and 'whorling' of actin thin filaments. The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability in clinical phenotype among patients with different mutations in ACTA1 suggested that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggested that alpha-actin genotype is not the sole determinant of phenotype, however.
In a report of the 2002 conference on nemaline myopathy, Wallgren-Pettersson and Laing (2003) stated that 59 mutations in the ACTA1 gene had been identified. Ninety percent of families had a diagnosis of nemaline myopathy, 11% had a diagnosis of actin myopathy, and 11% had a diagnosis of intranuclear rod myopathy. The findings underscored the phenotypic variability caused by mutations in the ACTA1 gene. Among the patients with nemaline myopathy, the severe form was the most common, but mild and typical forms were also represented, and some patients had unusual associated features. Most cases were sporadic, but there were examples of both autosomal dominant and autosomal recessive inheritance. No obvious genotype/phenotype correlations were observed.
Agrawal et al. (2004) found 29 ACTA1 mutations in 28 of 109 (approximately 25%) patients with nemaline myopathy. Of the whole group, ACTA1 mutations were responsible for 14 of 25 (56%) of the severe congenital cases. Ten patients with ACTA1 mutations had 'typical disease,' defined as onset in infancy or childhood with delayed milestones and survival into adulthood, and 1 patient had adult onset. Four of the families with ACTA1 mutations showed autosomal dominant inheritance; 1 family showed autosomal recessive inheritance; 2 families suggested incomplete penetrance; the remaining 21 patients had sporadic disease with heterozygous mutations. Muscle biopsy at 5 weeks of age from the patient with biallelic ACTA1 mutations with severe disease showed intense staining for cardiac alpha-actin. Agrawal et al. (2004) emphasized the phenotypic heterogeneity among patients with ACTA1 mutations.
Feng and Marston (2009) provided a review of ACTA1 mutations and concluded that there are no obvious functional or biochemical patterns seen in mutations that result in the same pathology. Although some mutations are predicted or have been shown to interfere with N-terminal processing, posttranslational folding, polymerization, or interaction with other proteins, there is often disagreement in studies between the structure and function of mutant proteins. There are no clear genotype/phenotype correlations.
By homologous recombination, Crawford et al. (2002) disrupted the skeletal actin gene in mice. Newborn skeletal muscles from null mice were similar to those of wildtype mice in size, fiber type, and ultrastructural organization. Both hemizygous and homozygous null animals showed an increase in cardiac and vascular actin (102620) mRNA in skeletal muscle, with no skeletal actin mRNA present in null mice. The null animals appeared normal at birth and could breathe, walk, and suckle. However, the compensation provided by expression of vascular and cardiac actins was insufficient to support adequate skeletal muscle growth and/or function. Within 4 days, all null mice showed a markedly lower body weight than normal littermates, and some developed scoliosis. All mice lacking skeletal actin died in the early neonatal period. They showed a loss of glycogen and reduced brown fat, consistent with malnutrition leading to death.
Ravenscroft et al. (2011) and Ravenscroft et al. (2011) generated mutant mice harboring a D286G mutation in the ACTA1 gene (102610.0025). Mice expressing the mutant protein at 25% of the total alpha-actin pool were less active than controls, but had a normal life span. Mice expressing the mutant protein at 45% of the alpha-actin pool had severe muscle weakness leading to early death. Skeletal muscle showed extensive structural abnormalities similar to those observed in humans with the disorder. The findings suggested a correlation between mutant ACTA1 protein load and disease severity.
Nguyen et al. (2011) generated mutant mice carrying the ACTA1 H40Y mutation (102610.0026) and found that they developed clinical features of severe congenital myopathy.
In 2 infant sibs (family 5) with autosomal recessive congenital myopathy-2B (CMYP2B; 620265) leading to death at 5 and 19 days of age, Nowak et al. (1999) identified compound heterozygous missense mutations in the ACTA1 gene: a T-to-C transition in exon 3, resulting in a leu94-to-pro (L94P) substitution, inherited from the unaffected father, and an A-to-G transition in exon 5, resulting in a glu259-to-val (E259V; 102610.0005) substitution, inherited from the unaffected mother.
Sparrow et al. (2003) noted that both the L94P and E259V mutations are buried residues that likely affect the internal packing of actin and may thus disrupt the structure of the protein. These mutant proteins may be so significantly impaired that they did not cause a dominant-negative effect in the carrier parents.
In a mother and her 2 children (family 6) with autosomal dominant congenital myopathy-2A (CMYP2A; 161800), Nowak et al. (1999) identified a heterozygous A-to-G transition in exon 3 of the ACTA1 gene, resulting in an asn115-to-ser (N115S) substitution.
Ilkovski et al. (2001) reported a 35-year-old woman (family A, patient 5) with the N115S mutation. She had typical congenital myopathy with neonatal onset of feeding difficulties, respiratory tract infections, hypotonia, facial diplegia, and proximal muscle weakness in the first weeks of life. Her disease was very slowly progressive or nonprogressive. She had 2 affected children with the mutation, a daughter (patient 6) aged 19 years and a son (patient 7) aged 4 years at the time of the report. The daughter had onset of disease at age 6 years, with mild proximal weakness and frequent falls, and developed progressive scoliosis requiring surgery at age 14 years. The son had features of congenital myopathy in infancy and showed nonprogressive weakness with improvement of mild nocturnal hypoventilation over time. The intrafamilial variability observed suggested that the ACTA1 genotype is not the sole determinant of the phenotype and that modifying factors, both genetic and stochastic influence the clinical presentation.
In a patient (P1) with severe infantile congenital myopathy-2C (CMYP2C; 620278), previously reported as patient 2 by Goebel et al. (1997), Nowak et al. (1999) identified a de novo heterozygous G-to-C transversion in exon 2 of the ACTA1 gene, resulting in a gly15-to-arg (G15R) substitution. The patient was delivered by emergency Cesarean section at 37 weeks' gestation due to maternal polyhydramnios, had severe hypotonia necessitating ventilatory support, and died at age 3 months. Postmortem examination excluded spinal muscular atrophy. Muscle biopsy showed large areas of sarcoplasm devoid of normal myofibrils and mitochondria, and replaced with dense masses of thin filaments that were immunoreactive to actin. Central cores, obvious rods, ragged-red fibers, and necrosis were absent.
In a 7.5-year-old patient (P2) with severe infantile congenital myopathy-2C (CMYP2C; 620278) originally reported as P1 by Goebel et al. (1997), Nowak et al. (1999) identified a de novo heterozygous G-to-C transversion in exon 4 of the ACTA1 gene, resulting in a val163-to-leu (V163L) substitution. The patient was hypotonic from birth, had atrophy of the pelvic and shoulder girdle muscles, a high-arched palate, and cardiomyopathy. At 4.5 years, he could walk and sit unaided. Muscle biopsy showed subsarcolemmal regions that were devoid of oxidative activity and filled with actin-immunopositive densely packed thin filaments. Intranuclear nemaline rods were also present (Goebel et al., 1997). The same amino acid substitution due to a different nucleotide change was observed in another patient with the disorder who died at 4 months of age (see 102610.0024).
For discussion of the glu259-to-val (E259V) mutation in the ACTA1 gene that was found in compound heterozygous state in 2 infant sibs with fatal autosomal recessive congenital myopathy-2B (CMYP2B; 620265) by Nowak et al. (1999), see 102610.0001.
In a patient with CMYP2B resulting in death at 2 months of age, Sparrow et al. (2003) identified compound heterozygous mutations in the ACTA1 gene: E259V and a 1-bp deletion (102610.0020).
In a patient (P1) with severe infantile congenital myopathy-2C (CMYP2C; 620278), who died at the age of 6 months of respiratory failure, Ilkovski et al. (2001) identified a de novo heterozygous A-to-C transversion in the ACTA1 gene, resulting in an ile357-to-leu (I357L) substitution. This female infant was born with hypotonia, minimal spontaneous movements, and fractures of both femurs. She did not achieve motor milestones and required a feeding tube.
In a 10-year-old boy (P3) with childhood onset of congenital myopathy-2A (CMYP2A1; 161800), Ilkovski et al. (2001) identified a de novo heterozygous G-to-T transversion in the ACTA1 gene, resulting in a gly268-to-cys (G268C) substitution. The patient had no problems during the neonatal period, but presented at age 5 years with inability to run and frequent falls. He did not have feeding or respiratory difficulties. At age 10, he had slowly progressive weakness with involvement of proximal muscles.
In a 45-year-old man (P4) with typical congenital myopathy-2A (CMYP2A; 161800), Ilkovski et al. (2001) identified a de novo heterozygous C-to-G transversion in the ACTA1 gene, resulting in an ile136-to-met (I136M) substitution. Although he had infantile onset and delayed motor development, his weakness was nonprogressive, and he was physically active as an adult and regularly engaged in long-distance competitive cycling. He had a weak cough and frequent respiratory infections. Echocardiography was normal. Nowak et al. (2013) noted that the muscle fibers were hypertrophied in the patient reported by Ilkovski et al. (2001), suggesting that both exercise and muscle fiber hypertrophy may be beneficial for patients with certain ACTA1 mutations.
In 11 affected members in 4 generations and 8 separate sibships of a German family with autosomal dominant congenital myopathy-2A (CMYP2A; 161800), Kaindl et al. (2004) identified a heterozygous c.110G-T transversion in exon 2 of the ACTA1 gene, resulting in an asp1-to-tyr (D1Y) substitution at a highly conserved residue in the mature protein.
In 5 affected members spanning 3 generations of a Chinese family with autosomal dominant congenital myopathy-2A (CMYP2A; 161800), Kaindl et al. (2004) identified a heterozygous c.1110A-C transversion in the ACTA1 gene, resulting in a glu334-to-ala (E334A) substitution at a conserved residue. Two members of the family developed adult-onset hypertrophic cardiomyopathy and respiratory insufficiency.
In an Australian patient (P1) with severe infantile congenital myopathy-2C (CMYP2C; 620278), Laing et al. (2004) identified a heterozygous A-to-T transversion in exon 6 of the ACTA1 gene, resulting in an asp292-to-val (D292V) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient died of respiratory failure at 3.5 years of age. Muscle biopsy showed congenital fiber-type disproportion (CFTD).
Using mass spectrometry and gel electrophoresis to examine patient skeletal muscle, Clarke et al. (2007) determined that D292V-actin accounted for 50% of total sarcomeric actin. In vitro assays showed that D292V-actin resulted in decreased motility due to abnormal interactions between actin and tropomyosin, with tropomyosin stabilized in the 'off' position. Cellular transfection studies demonstrated that the mutant protein incorporated into actin filaments and did not result in increased actin aggregation or disruption of the sarcomere. Clarke et al. (2007) concluded that ACTA1 mutations resulting in congenital myopathy cause weakness by interfering with sarcomeric function rather than structure.
In a Japanese patient (P2) with severe infantile congenital myopathy-2C (CMYP2C; 620278), Laing et al. (2004) identified a heterozygous T-to-C transition in exon 5 of the ACTA1 gene, resulting in a leu221-to-pro (L221P) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient required continuous ventilation and tube feeding; she died at 1.1 years of age. Muscle biopsy showed congenital fiber-type disproportion (CFTD).
In a 3-year-old Japanese patient (P3) with severe infantile congenital myopathy-2C (CMYP2C; 620278). Laing et al. (2004) identified a heterozygous C-to-T transition in exon 7 of the ACTA1 gene, resulting in a pro332-to-ser (P332S) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient had severe hypotonia with no head control and was bedridden with a feeding tube and continuous ventilation by tracheostomy. Muscle biopsy showed congenital fiber-type disproportion (CFTD).
In affected members of a family with autosomal dominant typical congenital myopathy-2A (CMYP2A; 161800), Hutchinson et al. (2006) identified a heterozygous G-to-A transition in exon 4 of the ACTA1 gene, resulting in a val163-to-met (V163M) substitution. Other mutations have been reported in this codon (V163L; 102610.0004 and 102610.0024). Clinical features included hypotonia early in life, limb muscle weakness and atrophy, tall thin face, and high-arched palate. Skeletal muscle biopsies varied but tended to show intranuclear rods within myofibers.
By electron microscopy of muscle samples from patients reported by Hutchinson et al. (2006), Domazetovska et al. (2007) found mostly normal sarcomere structure with small areas of sarcomeric disarray. Immunohistochemical studies showed that the V163M mutation resulted in sequestration of sarcomeric and Z line proteins into intranuclear aggregates. There was some evidence of muscle regeneration, suggesting a compensatory effect. Cell culture studies showed similar findings. Transgenic V161M-mutant Drosophila were flightless with sarcomeric disorganization and altered Z line structure in muscle. The findings provided a mechanism for muscle weakness.
In a male infant with severe infantile congenital myopathy-2C (CMYP2C; 620278), Garcia-Angarita et al. (2009) identified heterozygosity for an allele carrying 2 de novo mutations in cis affecting adjacent nucleotides in exon 3 of the ACTA1 gene: a c.222G-T transversion, resulting in a glu74-to-asp (E74D) substitution, and a c.223C-T transition, resulting in a his75-to-tyr (H75Y) substitution. Neither unaffected parent carried either of the mutations; germline mosaicism could not be ruled out. Garcia-Angarita et al. (2009) noted that each mutation had previously been reported in isolation as causative for congenital myopathy, but had never been reported together on the same allele. The phenotype in their patient was severe, including decreased movements in utero, breech presentation, and congenital contractures. After birth, there was severe hypotonia, lack of spontaneous movements, and death from respiratory failure at age 2 months. Skeletal muscle biopsy showed myofibrillar disorganization and nemaline rods.
In an infant with severe infantile congenital myopathy-2C (CMYP2C; 620278) who presented with an atypical phenotype of stiffness and hypertonicity, Jain et al. (2012) identified a de novo heterozygous c.984G-C transversion in the ACTA1 gene, resulting in a lys328-to-asn (K328N) substitution (K326N in the mature protein). Patient biopsy showed nemaline bodies and 32% mutant actin. In vitro motility analysis of actin thin filaments derived from the patient's tissue showed increased sensitivity to calcium, indicating an activated state. Expression of the mutant in mouse muscle cells did not result in the formation of rod-like structures, suggesting a different mechanism of nemaline body formation. Medical treatment was ineffective, and the patient died at age 9 months in an asystolic episode. The report expanded the phenotypic spectrum associated with ACTA1 mutations to include stiffness, rigidity, and hypertonicity.
In a 9-year-old Japanese boy with congenital myopathy-2A (CMYP2A; 161800) who developed fatal dilated cardiomyopathy, Gatayama et al. (2013) identified a heterozygous c.1074G-T transversion in exon 7 of the ACTA1 gene, resulting in a trp358-to-cys (W358C) substitution. The parents were unaffected and the mutation was not found in 50 Japanese controls. Functional studies of the variant were not performed. The patient had normal motor development in early childhood, but showed mild nonprogressive skeletal muscle weakness, such as slowed running compared to his peers. Other features included hypotonia, myopathic facies, high-arched palate, and mild weakness of proximal and distal muscles. He presented at age 9 years with acute deterioration of cardiac function, and died of cardiac failure 6 months later. Postmortem examination of cardiac muscle showed variation in myocardial fiber size and a few electron-dense fine structures related to Z lines. Skeletal muscle biopsy had previously shown typical nemaline rods. Gatayama et al. (2013) noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations.
In affected members of a large family with scapulohumeroperoneal myopathy (SHPM; 616852), originally reported by Armstrong et al. (1966), Zukosky et al. (2015) identified a heterozygous c.591C-A transversion in exon 4 of the ACTA1 gene, resulting in a glu197-to-asp (E197D) substitution. The mutation was found by a combination of linkage analysis and whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP or ExAC databases. Transfection of the mutation into COS-7 cells showed that the mutant protein had normal actin localization and did not form nemaline rods. Injection of the mutation into zebrafish embryos did not result in any morphologic abnormalities or abnormal muscle histology up to 6 days after fertilization. Zukosky et al. (2015) postulated that a fundamentally different pathogenic process than changes in actin cytoarchitecture or rod formation was responsible for the phenotype, such as changes in interaction or force generation, actin filament stability, or differences in the directionality of actin filament growth.
In an infant with severe autosomal recessive congenital myopathy-2B (CMYP2B; 620265) resulting in death from respiratory failure at 22 months of age, Sparrow et al. (2003) identified a homozygous mutation in exon 2 of the ACTA1 gene, resulting in an arg39-to-ter (R39X) substitution. Nowak et al. (2007) also reported this patient, stating that he was born of consanguineous French Gypsy parents. The mutation was a c.121C-T transition, resulting in an arg41-to-ter (R41X) substitution.
In a patient with severe autosomal recessive congenital myopathy-2B (CMYP2B; 620265) resulting in death at 2 months of age, Sparrow et al. (2003) identified compound heterozygous mutations in the ACTA1 gene: a 1-bp deletion (g.2221delG), resulting in a frameshift at Ala144, and E259V (102610.0005). Functional studies of the variants were not performed, but the frameshift mutation was predicted to result in a loss-of-function effect.
In 3 sibs with severe autosomal recessive congenital myopathy-2B (CMYP2B; 620265) resulting in death in the first months of life, Sparrow et al. (2003) identified a homozygous G-to-T transversion (g.2891G-T) in the splice site junction of intron 5 and exon 6, predicted to result in a splicing abnormality and a loss of function. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed, but it was predicted to have a loss-of-function effect.
In 5 patients from 4 unrelated consanguineous families with autosomal recessive congenital myopathy-2B (CMYP2B; 620265), Nowak et al. (2007) identified a homozygous 1-bp deletion (c.541delG) in the ACTA1 gene, predicted to result in a frameshift and premature termination (Asp181fsTer10). In cases where DNA was available, the unaffected parents were heterozygous for the mutation. The families were of Pakistani and Indian British origin, and haplotype analysis was consistent with a founder effect. Skeletal muscle biopsy from some of the patients showed absence of the ACTA1 protein with increased expression of cardiac alpha-actin (ACTC1; 102540), likely reflecting a compensatory mechanism.
In 2 brothers, born of consanguineous Sri Lankan parents, with autosomal recessive congenital myopathy-2B (CMYP2B; 620265), O'Grady et al. (2015) identified a homozygous c.460G-C transversion in the ACTA1 gene, resulting in a val154-to-leu (V154L) substitution in a residue near the ATP-binding pocket and hinge region. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous parents were unaffected. Functional studies of the variant were not performed, but it was predicted to be deleterious. Immunostaining and Western blot analysis of patient muscle showed normal levels of skeletal muscle ACTA1 and upregulated expression of cardiac alpha-actin (ACTC1; 102540). Of note, one of the brothers carried a heterozygous missense S388G variant in the SEPN1 gene. These sibs had a longer survival than most patients with recessive ACTA1 mutations: one died at age 6 years and the other was alive and ambulatory at age 34. O'Grady et al. (2015) noted that previously reported patients with biallelic ACTA1 mutations had functional 'null' variants and made no ACTA1 protein. Survival after birth was attributed to persistence of cardiac ACTC1 in the skeletal muscle of these children.
In a patient (P3) with severe infantile congenital myopathy-2C (CMYP2C; 620278) originally reported as P3 by Goebel et al. (1997), Nowak et al. (1999) identified a heterozygous G-to-T transversion in exon 4 of the ACTA1 gene, resulting in a val163-to-leu (V163L) substitution. This child was hypotonic from birth, had cardiomegaly, and died of cardiorespiratory insufficiency at age 4 months. Muscle biopsy showed a type-1 fiber predominance, subsarcolemmal masses of thin filaments, and intranuclear nemaline rods (Goebel et al., 1997). The same amino acid substitution due to a different nucleotide change was observed in another patient with the disorder who was still alive at 7.5 years of age (see 102610.0004).
In a patient (patient 17) with severe infantile congenital myopathy-2C (CMYP2C; 620278), Nowak et al. (1999) identified a heterozygous A-to-G transition in exon 6 of the ACTA1 gene, resulting in an asp286-to-gly (D286G) substitution. The patient died at 9 months of age. Parental DNA was not available for study, but the mutation likely occurred de novo.
In a male infant (25-1) with CMYP2C, Agrawal et al. (2004) identified a heterozygous c.966A-G transition in the ACTA1 gene, resulting in a D286G substitution. There was no family history of the disease, and this was an isolated case, likely due to a de novo mutation (parental DNA was not available for study). The patient had hypotonia, joint contractures, femur fracture, no movement, and no respiratory effort at birth. He was tube-fed and required ventilatory support until his death at 6 days of age. Muscle biopsy showed marked fiber size variability, disruption of myofibrils, and nemaline bodies.
Ravenscroft et al. (2011) and Ravenscroft et al. (2011) generated mutant mice harboring the D286G mutation. Mice expressing the mutant protein at 25% of the total alpha-actin pool were less active than controls, but had a normal life span. Mice expressing the mutant protein at 45% of the alpha-actin pool had severe muscle weakness leading to early death. Skeletal muscle showed extensive structural abnormalities similar to those observed in humans with the disorder. The findings suggested a correlation between mutant ACTA1 protein load and disease severity.
In a patient (P4) with severe infantile congenital myopathy-2C (CMYP2C; 620278) who died at 2 months of age, Nowak et al. (1999) identified a de novo C-to-T transition in exon 2 of the ACTA1 gene, resulting in a his40-to-tyr (H40Y) substitution.
Nguyen et al. (2011) generated mutant mice carrying the ACTA1 H40Y mutation and found that they developed clinical features of severe congenital myopathy.
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