| *102610 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTIN, ALPHA, SKELETAL MUSCLE 1; ACTA1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ASMA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: ACTA1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 1q42.13 Genomic coordinates (GRCh37): 1:229,566,991 - 229,569,842 (from NCBI) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biochemical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle, and nonmuscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin in dilated cardiomyopathy (102540.0001) and hypertrophic cardiomyopathy (102540.0003); in cardiac myosin in hypertrophic cardiomyopathy (160760.0001); and in nonmuscle myosin in deafness (276903.0001). In patients with nemaline myopathy (NEM3; 161800), Nowak et al. (1999) identified 15 different missense mutations in the ACTA1 gene (see, e.g., 102610.0001). The missense mutations in ACTA1 were distributed throughout all 6 coding exons and some involved known functional domains of actin. Approximately half of the patients died within their first year, but 2 female patients had survived into their thirties and had children. Nowak et al. (1999) identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family documenting dominant inheritance comprised a 33-year-old affected mother with 2 affected and 2 unaffected children (102610.0002). In another family, the clinically unaffected father was a somatic mosaic for the mutation seen in both of his affected children. They identified recessive mutations in 1 family in which the 2 affected sibs had heterozygous mutations in 2 different exons, 1 paternally and the other maternally inherited (102610.0001; 102610.0005). They also identified de novo mutations in 7 sporadic probands for which it was possible to analyze parental DNA. In affected members of 2 families with an autosomal dominant 'core only' myopathy, Kaindl et al. (2004) identified 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. By immunoblot analysis, Ilkovski et al. (2004) showed that muscle from nemaline myopathy (NM) patients 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)-, V163M-, 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. (2004) identified mutations in the ACTA1 gene (102610.0011-102610.0013) in 3 unrelated patients with a severe form of congenital fiber-type disproportion (255310). None of the patients had nemaline rods on muscle biopsy. 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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-onset 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% 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 recessively inherited ACTA1 patient with severe disease showed intense staining for cardiac 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, LEU94PRO [dbSNP:rs121909519] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 infant sibs with severe autosomal recessive nemaline myopathy-3 (NEM3; 161800) leading to death at 5 and 19 days of age, respectively, Nowak et al. (1999) identified compound heterozygosity for 2 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, ASN115SER [dbSNP:rs121909520] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a mother and her 2 children who had nemaline myopathy (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. One of the children with a severe form of the disorder was alive at 3 years; the mother and the other child had milder forms, and were alive at 33 and 18 years of age, respectively. Ilkovski et al. (2001) reported a 35-year-old woman with the N115S mutation. She had typical congenital nemaline 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 an affected younger sib and an affected daughter, consistent with autosomal dominant inheritance. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 MYOPATHY, ACTIN, CONGENITAL, WITH EXCESS OF THIN MYOFILAMENTS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, GLY15ARG [dbSNP:rs121909521] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In patient 2 with a congenital actin myopathy (see 161800), reported by Goebel et al. (1997), Nowak et al. (1999) identified a 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 (253300). 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, VAL163LEU [dbSNP:rs121909522] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 unrelated patients with nemaline myopathy-3 (161800) originally reported by Goebel et al. (1997), Nowak et al. (1999) identified a heterozygous val163-to-leu (V163L) substitution in the ACTA1 gene. However, the amino acid substitution was caused by different nucleotide changes: in a child still alive at 7.5 years of age, codon 163 was changed from GTG (val) to CTG (leu); in an infant who died at 4 months of age, codon 163 was changed from GTG (val) to TTG (leu). One patient was hypotonic from birth, had atrophy of the pelvic and shoulder girdle muscles, and cardiomyopathy. He also had a high-arched palate. 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. The second patient 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, GLU259VAL [dbSNP:rs121909523] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 102610.0001 and Nowak et al. (1999). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, ILE357LEU [dbSNP:rs121909524] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a child with severe congenital nemaline myopathy (161800) who died at the age of 6 months of respiratory failure, Ilkovski et al. (2001) identified a heterozygous de novo mutation in the ACTA1 gene, resulting in an ile357-to-leu (I357L) substitution. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, GLY268CYS [dbSNP:rs121909525] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a male patient with childhood onset of nemaline myopathy (161800), Ilkovski et al. (2001) identified a heterozygous gly268-to-cys (G268C) substitution in the ACTA1 gene. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, ILE136MET [dbSNP:rs121909526] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ilkovski et al. (2001) identified a heterozygous ile136-to-met (I136M) substitution in the ACTA1 gene in a 45-year-old man with nemaline myopathy (161800). 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 MYOPATHY, ACTIN, CONGENITAL, WITH CORES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, ASP1TYR [dbSNP:rs121909527] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 11 affected members in 4 generations and 8 separate sibships of a German family with autosomal dominant congenital myopathy with cores, part of the phenotypic spectrum of nemaline myopathy 3 (161800), Kaindl et al. (2004) identified a heterozygous 110G-T transversion in the ACTA1 gene, resulting in an asp1-to-tyr (D1Y) substitution in the mature protein. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0010 MYOPATHY, ACTIN, CONGENITAL, WITH CORES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, GLU334ALA [dbSNP:rs121909528] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 5 affected members spanning 3 generations of a Chinese family with autosomal dominant congenital myopathy with cores, part of the phenotypic spectrum of nemaline myopathy 3 (161800), Kaindl et al. (2004) identified a 1110A-C transversion in the ACTA1 gene, resulting in a glu334-to-ala (E334A) substitution. Two members of the family developed adult-onset hypertrophic cardiomyopathy and respiratory insufficiency. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0011 MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, ASP292VAL [dbSNP:rs121909529] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with severe congenital fiber-type disproportion myopathy (255310), 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. DNA was not available from any of the patient's relatives. 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 CFTD cause weakness by interfering with sarcomeric function rather than structure. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0012 MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, LEU221PRO [dbSNP:rs121909530] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with severe congenital fiber-type disproportion myopathy (255310), 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. DNA was not available from any of the patient's relatives. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0013 MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, PRO332SER [dbSNP:rs121909531] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with severe congenital fiber-type disproportion myopathy (255310), 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. DNA was not available from any of the patient's relatives. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0014 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, VAL163MET [dbSNP:rs121909532] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a family with nemaline myopathy-3 (161800) associated with intranuclear rods on muscle biopsy, 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. Another mutation has been reported in this codon (V163I; 102610.0004). 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0015 NEMALINE MYOPATHY 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACTA1, GLU74ASP AND HIS75TYR | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a male infant with severe fatal nemaline myopathy (NEM3; 161800), 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 222G-T transversion, resulting in a glu74-to-asp (E74D) substitution, and a 223C-T transition, resulting in a his75-to-tyr (H75Y) substitution. Neither unaffected parent carried either of the mutations, suggesting possible germline mosaicism. Garcia-Angarita et al. (2009) noted that each mutation had previously been reported in isolation as causative for nemaline 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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