HGNC Approved Gene Symbol: ACTN2
Cytogenetic location: 1q43 Genomic coordinates (GRCh38): 1:236,686,499-236,764,631 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q43 | Cardiomyopathy, dilated, 1AA, with or without LVNC | 612158 | Autosomal dominant | 3 |
| Cardiomyopathy, hypertrophic, 23, with or without LVNC | 612158 | Autosomal dominant | 3 | |
| Congenital myopathy 8 | 618654 | Autosomal dominant | 3 | |
| Myopathy, distal, 6, adult onset | 618655 | Autosomal dominant | 3 |
The ACTN2 gene encodes alpha-actinin-2, which is highly expressed in the sarcomeric Z-disk or Z-line in both cardiac and skeletal muscle, where it plays important structural and functional roles in the sarcomere and contractile apparatus (summary by Lornage et al., 2019).
Alpha-actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane (see ACTN1; 102575). In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. Beggs et al. (1992) characterized 2 human muscle-specific alpha-actinin genes, ACTN2 and ACTN3 (102574). They identified 3 ACTN2 transcripts that differed only in their use of polyadenylation signals. The deduced 894-amino acid protein has a calculated molecular mass of about 104 kD. ACTN2 has an N-terminal actin-binding domain of about 250 amino acids, followed by 4 central repeats and 2 EF-hand motifs near the C terminus. Northern blot analysis of mouse tissues detected Actn2 expression in skeletal muscle and heart, but not in brain, liver, kidney, or small intestine. Two major ACTN2 bands were detected in human fetal skeletal muscle.
Seto et al. (2011) stated that the central repeats of ACTN2 are spectrin (see 182860)-like repeats that form a rod domain.
Using somatic cell hybrids, Beggs et al. (1992) mapped the ACTN2 and ACTN3 genes to chromosomes 1 and 11, respectively. In situ hybridization placed the ACTN2 locus at 1q42-q43. Beggs et al. (1992) identified a polymorphic (CA)n repeat within the ACTN2 gene and used it to position the ACTN2 gene on the CEPH linkage map of chromosome 1.
Mills et al. (2001) mapped the 4 murine actinin orthologs, which were all located at evolutionarily conserved syntenic regions for the 4 human genes.
Mills et al. (2001) observed that murine Actn2 and Actn3 were differentially expressed, spatially and temporally, during embryonic development and, in contrast to humans, alpha-actinin-2 expression did not completely overlap with alpha-actinin-3 in postnatal skeletal muscle, suggesting independent function.
Seto et al. (2011) found that expression of Actn2 was upregulated in Actn3 -/- mouse extensor digitorum longus muscle such that the total sarcomeric content of alpha-actinin was unchanged. Actn3 -/- muscle was susceptible to contraction-induced damage compared with wildtype. The Z-disc proteins Zasp (LDB3; 605906), titin (TTN; 188840), and vinculin (VCL; 193065) bound more avidly to Actn2 than to Actn3, suggesting a biochemical basis for altered mechanics and fragility in Actn3 -/- muscle.
Cardiac Phenotypes
In a 7-year-old girl who died of dilated cardiomyopathy (CMD1AA; 612158) and was negative for mutation in 8 known cardiomyopathy genes, Mohapatra et al. (2003) identified heterozygosity for a missense mutation in the ACTN2 gene (Q9R; 102573.0001).
In 3 sporadic patients with hypertrophic cardiomyopathy (CMH23; see 612158), Theis et al. (2006) identified heterozygous missense mutations in the ACTN2 gene (102573.0002-102573.0004).
In affected members of a large 3-generation Australian family with clinically heterogeneous CMH mapping to chromosome 1, Chiu et al. (2010) identified heterozygosity for a missense mutation in the ACTN2 gene (A119T; 102573.0005). Screening of an additional 297 CMH probands identified 3 heterozygous missense mutations that segregated with disease in the respective families (see, e.g., 102573.0003 and 102573.0006).
In 4 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including CMD, left ventricular noncompaction (LVNC), ventricular fibrillation, and sudden death, Bagnall et al. (2014) identified heterozygosity for the same A119T substitution in the ACTN2 gene that had previously been detected in an apparently unrelated Australian family with clinically heterogeneous CMH by Chiu et al. (2010). Haplotype analysis was consistent with a common ancestor for the 2 Australian families.
In a large 4-generation Italian family with clinically heterogeneous cardiomyopathic disease comprising variable combinations of asymmetric left ventricular hypertrophy (LVH) consistent with CMH, early-onset supraventricular arrhythmias and atrioventricular (AV) block, and regional LVNC, Girolami et al. (2014) performed next-generation sequencing and identified heterozygosity for a missense mutation in ACTN2 (M228T; 102573.0007). The mutation, which segregated fully with disease in the family, was not found in 570 control alleles.
Congenital Myopathy 8
In 2 unrelated patients with congenital myopathy-8 (CMYP8; 618654), Lornage et al. (2019) identified de novo heterozygous mutations in exon 18 of the ACTN2 gene (L727R, 102573.0008 and an in-frame deletion, 102573.0009); both were located in the fourth spectrin repeat. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. In addition, patient 1 was heterozygous and patient 2 was homozygous for the common R577X polymorphism in the ACTN3 gene (102574.0001). Western blot analysis of skeletal muscle from the patient with the L727R mutation and analysis of cells transfected with that mutation showed normal protein expression, dimerization, and localization. However, Lornage et al. (2019) found that expression of human mutant ACTN2 L727R in zebrafish embryos resulted in hatching defects, smaller myotome, dorsal curvature, and impaired motor function, although levels of protein expression were not affected. Skeletal muscle from mutant fish showed significant myofibrillar disarray, sarcomeric disorganization, abnormal Z-lines, and abnormal actin-myosin interaction compared to wildtype. AAV-mediated expression of the mutation in skeletal muscle of 3-week-old mice resulted in reduced maximal force as well as abnormal Z-line organization and core formation. The findings in both animal models recapitulated the specific phenotype in humans.
Adult-Onset Distal Myopathy 6, Autosomal Dominant
In affected members of 3 unrelated families from northern Spain with autosomal dominant adult-onset distal myopathy-6 (MPD6; 618655), Savarese et al. (2019) identified a heterozygous missense mutation in the ACTN2 gene (C487R; 102573.0010). In a Swedish father and daughter with a similar disorder, they identified a different heterozygous mutation in the ACTN2 gene (L131P; 102573.0011). The variants, which were found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families and were not found in the gnomAD database. Functional studies of the variants were not performed.
Mutations in the dystrophin gene (DMD; 300377) result in Duchenne muscular dystrophy. Dystrophin is a multidomain protein that functions to stabilize the sarcolemmal membrane during muscle contraction. Dystrophin shares considerable homology with alpha-actinin. To explore the hypothesis that the dystrophin rod domain acts as a spacer region, Harper et al. (2002) expressed a chimeric micro-dystrophin transgene containing the 4-repeat rod domain of alpha-actinin-2 in mdx mice. The transgene was incapable of correcting the morphologic pathology of the mdx mouse, but still functioned to assemble the dystrophin-glycoprotein complex at the membrane and provided some protection from contraction-induced injury. The authors concluded that different spectrin-like repeats are not equivalent, and proposed that the dystrophin rod domain is not merely a spacer but likely contributes an important mechanical role to overall dystrophin function.
Gupta et al. (2012) performed targeted knockdown of actn2 in zebrafish and observed developmental defects in eye, heart, and skeletal muscle. Morphant fish were largely immotile with a blunted touch-evoked response, suggesting a significant degree of overall muscle weakness. Morphants consistently exhibited smaller eyes, enlarged hearts with reduced heartbeat, and abnormal organization of skeletal muscles. Skeletal muscles showed a significant decrease in birefringence, and histologic analysis of longitudinal sections revealed disorganized muscle fibers, with occasional fibers completely lacking in myofibrillar organization; on electron microscopy, many fibers showed reduced sarcomeric organization and rounded multiple nuclei. The cardiac phenotype presented as a reduction in heart rate between 1 and 2 days postfertilization (dpf), and by 3 dpf, morphants exhibited clearly enlarged hearts; histologic examination showed enlarged hearts with both atrial and ventricular dilation and remarkably thin walls, and there was a marked decrease in the size and number of sarcomeric assemblies in both atrial and ventricular morphant cardiomyocytes by electron microscopy. The morphants also exhibited smaller eyes than control fish, with absent or undifferentiated photoreceptors and disorganized inner layers at 3 dpf; the lens lacked the normal crystalline organization, and many of the fiber cells retained their nuclei. The phenotype could be rescued by overexpression of actn2 but not actn3 mRNAs.
In a 7-year-old girl who died of dilated cardiomyopathy (CMD1AA; 612158), Mohapatra et al. (2003) identified heterozygosity for a 26A-G transition in exon 1 of the ACTN2 gene, resulting in a substitution of arg for the conserved residue gln9 (Q9R). The mutation was not found in the unaffected mother or in 200 controls; DNA was not available from the father, who had died from idiopathic CMD at 42 years of age.
In a man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see 612158) at 31 years of age, Theis et al. (2006) identified heterozygosity for a gly111-to-val (G111V) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 20 mm, with a sigmoid septal shape. He was treated with myectomy, and histopathologic analysis showed marked myocyte hypertrophy, focal myocyte disarray, and endocardial fibrosis. There was no family history of CMH or sudden cardiac death.
In a man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see 612158) at 32 years of age, Theis et al. (2006) identified heterozygosity for a thr495-to-met (T495M) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 16 mm, with a sigmoid septal shape. He was treated with myectomy, and histopathologic analysis showed marked endocardial fibrosis, myocyte hypertrophy, and interstitial fibrosis. There was no family history of CMH or sudden cardiac death.
In a European and a South American proband with CMH, Chiu et al. (2010) identified heterozygosity for the T495M substitution in ACTN2, which the authors noted was located at a highly conserved residue within the second spectrin repeat of the rod domain. SNP analysis indicated that the mutation arose from different founders in the 2 families. One of the probands, who had an affected sister, also had a daughter who carried the T495M mutation. The 15-year-old girl had localized thickening of the interventricular septal wall, indicating early CMH. The other proband was a 20-year-old man with severe hypertrophy. His parents and sister were clinically unaffected but declined genetic testing. Chiu et al. (2010) noted that in contrast to the patient reported by Theis et al. (2006), none of these patients displayed sigmoidal morphology.
In a man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see 612158) at 18 years of age, Theis et al. (2006) identified heterozygosity for an arg759-to-thr (R759T) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 16 mm, with a sigmoid septal shape. He was treated with myectomy, but the histopathologic report was unavailable. There was no family history of CMH or sudden cardiac death.
Dilated Cardiomyopathy 1AA
In 4 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including dilated cardiomyopathy (CMD1AA; 612158), left ventricular noncompaction, ventricular fibrillation, and sudden death, Bagnall et al. (2014) identified heterozygosity for a G-A transition in the ACTN2 gene (chr1.236,882,307G-A, GRCh37), resulting in an ala119-to-thr (A119T) substitution. The mutation was also present in an asymptomatic 35-year-old female cousin of the proband, in whom cardiac evaluation at age 29 was normal, including electrocardiography, echocardiography, electrophysiologic study, and 7-day Holter monitor. Haplotype analysis was consistent with a common ancestor shared by this family and the Australian family reported by Chiu et al. (2010).
Familial Hypertrophic Cardiomyopathy 23
In affected members of a large 3-generation Australian family with clinically heterogeneous CMH mapping to chromosome 1 (CMH23; see 612158), Chiu et al. (2010) identified heterozygosity for a G-A transition in exon 3 of the ACTN2 gene, resulting in an A119T substitution at a highly conserved residue within the CH1 domain of the actin-binding domain. Overexpression of the A119T variant in stably transfected myoblast cells resulted in a significant increase in RNA markers of hypertrophy. Chiu et al. (2010) stated that in contrast to previously reported patients with ACTN2 mutations Theis et al. (2006), none of these patients displayed sigmoidal morphology; rather, they exhibited generally mild hypertrophy with a diverse distribution, involving the septum in some individuals, whereas others showed apical, concentric, or right ventricular hypertrophy, with progression to a dilated phenotype and severe heart failure in some cases.
In a 44-year-old woman with moderate hypertrophic cardiomyopathy (CMH23; see 612158), Chiu et al. (2010) identified heterozygosity for a glu628-to-gly (E628G) substitution at a highly conserved residue within the third spectrin repeat of the rod domain. The proband had 2 sons who also carried the mutation; 1 showed mild asymmetric septal hypertrophy with borderline voltage criteria for left ventricular hypertrophy on electrocardiogram, whereas the other son, who was only 15 years of age, was clinically normal.
In 11 affected members of a large 4-generation Italian family with clinically heterogeneous cardiomyopathic disease comprising variable combinations of asymmetric left ventricular hypertrophy consistent with hypertrophic cardiomyopathy (CMH23; see 612158) as well as early-onset supraventricular arrhythmias and AV block, and regional left ventricular noncompaction, Girolami et al. (2014) identified heterozygosity for a c.683T-C transition (c.683T-C, NM_001103.2) in the ACTN2 gene, resulting in a met228-to-thr (M228T) substitution at a conserved residue within the actin-binding domain. The mutation, which segregated fully with disease in the family, was not found in 570 control alleles.
In a 45-year-old man (patient 1) with congenital myopathy with structured cores and Z-line abnormalities (CMYP8; 618654), Lornage et al. (2019) identified a de novo heterozygous c.2180T-G transversion (c.2180T-G, NM_001103.3) in exon 18 of the ACTN2 gene, resulting in a leu727-to-arg (L727R) substitution at a conserved residue in the fourth spectrin repeat. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Western blot analysis of skeletal muscle and analysis of cells transfected with the L727R mutation showed normal protein expression, dimerization, and localization. Lornage et al. (2019) found that expression of human mutant ACTN2 L727R in zebrafish embryos resulted in hatching defects, smaller myotome, dorsal curvature, and impaired motor function, although levels of protein expression were not affected. Skeletal muscle from mutant fish showed significant myofibrillar disarray, abnormal Z-lines, and abnormal actin-myosin interaction compared to wildtype. AAV-mediated expression of the mutation in skeletal muscle of 3-week-old mice resulted in reduced maximal force as well as abnormal Z-line organization and core formation. The findings in both animal models recapitulated the specific phenotype in humans.
In a 40-year-old woman (patient 2) with congenital myopathy-8 (CMYP8; 618654), Lornage et al. (2019) identified a de novo heterozygous 33-bp in-frame deletion (c.2194_2226del, NM_001103.3) in exon 18 of the ACTN2 gene, resulting in an Ala732_Ile742del in the fourth spectrin repeat. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In affected members of 3 unrelated families from northern Spain with autosomal dominant adult-onset distal myopathy-6 (MPD6; 618655), Savarese et al. (2019) identified a heterozygous c.1459T-C transition (c.1459T-C, NM_001103) in the ACTN2 gene, resulting in a cys487-to-arg (C487R) substitution at a conserved residue in the second spectrin repeat, which is important for dimerization. The variant, which was found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not found in the gnomAD database. The families all came from the same small village, suggesting a possible founder effect. Functional studies of the variant were not performed, but cDNA analysis showed that the variant did not affect splicing.
In a Swedish father and daughter with autosomal dominant adult-onset distal myopathy-6 (MPD6; 618655), Savarese et al. (2019) identified a heterozygous c.392T-C transition (c.392T-C, NM_001103) in the ACTN2 gene, resulting in a leu131-to-pro (L131P) substitution in the actin-binding domain. The variant, which was found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
Bagnall, R. D., Molloy, L. K., Kalman, J. M., Semsarian, C. Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death. BMC Med. Genet. 15: 99, 2014. Note: Electronic Article. [PubMed: 25224718] [Full Text: https://doi.org/10.1186/s12881-014-0099-0]
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Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J. ACTN2 mutations cause 'multiple structured core disease' (MsCD). Acta Neuropath. 137: 501-519, 2019. [PubMed: 30701273] [Full Text: https://doi.org/10.1007/s00401-019-01963-8]
Mills, M. A., Yang, N., Weinberger, R. P., Vander Woude, D. L., Beggs, A. H., Easteal, S., North, K. N. Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy. Hum. Molec. Genet. 10: 1335-1346, 2001. [PubMed: 11440986] [Full Text: https://doi.org/10.1093/hmg/10.13.1335]
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