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URL of this page: https://medlineplus.gov/genetics/gene/acta1/

ACTA1 gene

actin alpha 1, skeletal muscle

Normal Function

The ACTA1 gene provides instructions for making skeletal alpha (α)-actin, which is part of the actin protein family. Actin proteins are important for cell movement and the tensing of muscle fibers (muscle contraction). These proteins also help maintain the cytoskeleton, which is the structural framework that determines cell shape and organizes cell contents.

Skeletal α-actin plays an important role in skeletal muscles, which are muscles that the body uses for movement. Within skeletal muscle cells, skeletal α-actin is an essential component of structures called sarcomeres. Sarcomeres are the basic units of muscle contraction. They are composed of thin filaments made up of actin and thick filaments that are made up of another protein called myosin. The thin and thick filaments overlap and undergo cycles of attachment and release that allow the thin filaments to slide past the thick filaments, which shortens the sarcomere and causes the muscle to contract.

Health Conditions Related to Genetic Changes

Actin-accumulation myopathy

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the ACTA1 gene have been found to cause actin-accumulation myopathy, which is a muscle disorder (myopathy) that affects the skeletal muscles. People with actin-accumulation myopathy have severe muscle weakness and weak muscle tone (hypotonia) throughout the body. Most of the pathogenic ACTA1 gene variants that cause actin-accumulation myopathy result in changes to single protein building blocks (amino acids) in the skeletal α-actin protein.

Researchers suggest that ACTA1 gene variants may affect the way the actin binds to ATP. ATP is a molecule that supplies energy for cell activities and is important for the formation of thin filaments from individual actin molecules. Dysfunctional actin-ATP binding may disrupt the normal formation of thin filaments. This can impair muscle contraction, leading to muscle weakness and the other signs and symptoms of actin-accumulation myopathy.

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Cap myopathy

Pathogenic variants in the ACTA1 gene can cause cap myopathy. People with cap myopathy have myopathy throughout their body, but it most severely affects the muscles of the face, neck, arms, and legs. Pathogenic ACTA1 gene variants cause cells to produce abnormal versions of proteins that may interfere with the proper assembly of thin filaments. Disorganized clusters of thin filaments form the cap-like structures that give this condition its name. The abnormal filament structure likely makes it difficult for skeletal muscles to contract, resulting in muscle weakness and the other signs and symptoms of cap myopathy.

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Congenital fiber-type disproportion

Pathogenic variants in the ACTA1 gene have been found to cause congenital fiber-type disproportion, a disorder that causes general muscle weakness that typically does not worsen over time. The ACTA1 gene variants that cause this condition lead to changes in single amino acids in skeletal α-actin. This causes cells to produce an abnormal version of the actin protein, which interferes with the function of normal actin proteins in the sarcomere. As a result, the function of the sarcomere is impaired and muscle contraction is disrupted. Impaired muscle contraction leads to muscle weakness in people with congenital fiber-type disproportion.

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Intranuclear rod myopathy

Pathogenic variants in the ACTA1 gene cause intranuclear rod myopathy. This condition is noticeable in infancy and causes severe muscle weakness. The pathogenic variants in the ACTA1 gene that cause intranuclear rod myopathy lead to changes in single amino acids in the skeletal α-actin protein. These changes result in rod-shaped accumulations of actin in the nucleus of muscle cells. Normally, actin is found in the fluid surrounding the nucleus (the cytoplasm); only small amounts are in the nucleus itself.

Researchers suggest that the ACTA1 gene variants that cause intranuclear rod myopathy interfere with the normal transport of actin out of the nucleus and into the cytoplasm, resulting in the accumulation of actin in the nucleus and the formation of intranuclear rods. The buildup of these rods can interfere with the normal functions of the nucleus, such as directing cell growth and producing proteins from genes. Abnormal accumulation of actin in the nucleus of muscle cells and a corresponding reduction of available actin in muscle fibers may impair muscle contraction and lead to the muscle weakness seen in people with intranuclear rod myopathy.

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Nemaline myopathy

Pathogenic variants in the ACTA1 gene have been found to cause nemaline myopathy. People with nemaline myopathy have myopathy throughout their bodies, but it most severely affects the muscles close to the center of the body (proximal muscles). Nemaline myopathy is the most common muscle disorder that is associated with ACTA1 gene variants. Some of the variants that cause this disorder alter the structure or function of skeletal α-actin, causing the protein to cluster together and form clumps (aggregates). These aggregates interfere with the normal functioning of muscle cells. Other ACTA1 gene variants prevent the production of any skeletal α-actin, impairing the muscle cells' ability to contract. By disrupting the process of muscle contraction, these variants cause muscle weakness and the other features of this condition.

Instead of several separate disorders, some researchers consider the disorders caused by pathogenic variants in the ACTA1 gene to be a single disorder with a spectrum of overlapping signs and symptoms and group them together under the umbrella term alpha-actinopathy.

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Other Names for This Gene

  • ACTA
  • NEM3

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Agrawal PB, Strickland CD, Midgett C, Morales A, Newburger DE, Poulos MA, Tomczak KK, Ryan MM, Iannaccone ST, Crawford TO, Laing NG, Beggs AH. Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol. 2004 Jul;56(1):86-96. doi: 10.1002/ana.20157. Citation on PubMed
  • Castiglioni C, Cassandrini D, Fattori F, Bellacchio E, D'Amico A, Alvarez K, Gejman R, Diaz J, Santorelli FM, Romero NB, Bertini E, Bevilacqua JA. Muscle magnetic resonance imaging and histopathology in ACTA1-related congenital nemaline myopathy. Muscle Nerve. 2014 Dec;50(6):1011-6. doi: 10.1002/mus.24353. Epub 2014 Oct 30. Citation on PubMed
  • Clarke NF, Ilkovski B, Cooper S, Valova VA, Robinson PJ, Nonaka I, Feng JJ, Marston S, North K. The pathogenesis of ACTA1-related congenital fiber type disproportion. Ann Neurol. 2007 Jun;61(6):552-61. doi: 10.1002/ana.21112. Citation on PubMed
  • Clayton JS, Johari M, Taylor RL, Dofash L, Allan G, Monahan G, Houweling PJ, Ravenscroft G, Laing NG. An Update on Reported Variants in the Skeletal Muscle alpha-Actin (ACTA1) Gene. Hum Mutat. 2024 Oct 28;2024:6496088. doi: 10.1155/2024/6496088. eCollection 2024. Citation on PubMed
  • Domazetovska A, Ilkovski B, Cooper ST, Ghoddusi M, Hardeman EC, Minamide LS, Gunning PW, Bamburg JR, North KN. Mechanisms underlying intranuclear rod formation. Brain. 2007 Dec;130(Pt 12):3275-84. doi: 10.1093/brain/awm247. Epub 2007 Oct 10. Citation on PubMed
  • Feng JJ, Marston S. Genotype-phenotype correlations in ACTA1 mutations that cause congenital myopathies. Neuromuscul Disord. 2009 Jan;19(1):6-16. doi: 10.1016/j.nmd.2008.09.005. Epub 2008 Oct 30. Citation on PubMed
  • Hung RM, Yoon G, Hawkins CE, Halliday W, Biggar D, Vajsar J. Cap myopathy caused by a mutation of the skeletal alpha-actin gene ACTA1. Neuromuscul Disord. 2010 Apr;20(4):238-40. doi: 10.1016/j.nmd.2010.01.011. Epub 2010 Mar 19. Citation on PubMed
  • Ilkovski B, Clement S, Sewry C, North KN, Cooper ST. Defining alpha-skeletal and alpha-cardiac actin expression in human heart and skeletal muscle explains the absence of cardiac involvement in ACTA1 nemaline myopathy. Neuromuscul Disord. 2005 Dec;15(12):829-35. doi: 10.1016/j.nmd.2005.08.004. Epub 2005 Nov 8. Citation on PubMed
  • Kaimaktchiev V, Goebel H, Laing N, Narus M, Weeks D, Nixon R. Intranuclear nemaline rod myopathy. Muscle Nerve. 2006 Sep;34(3):369-72. doi: 10.1002/mus.20521. Citation on PubMed
  • Koy A, Ilkovski B, Laing N, North K, Weis J, Neuen-Jacob E, Mayatepek E, Voit T. Nemaline myopathy with exclusively intranuclear rods and a novel mutation in ACTA1 (Q139H). Neuropediatrics. 2007 Dec;38(6):282-6. doi: 10.1055/s-2008-1065356. Citation on PubMed
  • Laing NG, Clarke NF, Dye DE, Liyanage K, Walker KR, Kobayashi Y, Shimakawa S, Hagiwara T, Ouvrier R, Sparrow JC, Nishino I, North KN, Nonaka I. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol. 2004 Nov;56(5):689-94. doi: 10.1002/ana.20260. Citation on PubMed
  • Laing NG, Dye DE, Wallgren-Pettersson C, Richard G, Monnier N, Lillis S, Winder TL, Lochmuller H, Graziano C, Mitrani-Rosenbaum S, Twomey D, Sparrow JC, Beggs AH, Nowak KJ. Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1). Hum Mutat. 2009 Sep;30(9):1267-77. doi: 10.1002/humu.21059. Citation on PubMed or Free article on PubMed Central
  • Nowak KJ, Sewry CA, Navarro C, Squier W, Reina C, Ricoy JR, Jayawant SS, Childs AM, Dobbie JA, Appleton RE, Mountford RC, Walker KR, Clement S, Barois A, Muntoni F, Romero NB, Laing NG. Nemaline myopathy caused by absence of alpha-skeletal muscle actin. Ann Neurol. 2007 Feb;61(2):175-84. doi: 10.1002/ana.21035. Citation on PubMed
  • Ochala J. Thin filament proteins mutations associated with skeletal myopathies: defective regulation of muscle contraction. J Mol Med (Berl). 2008 Nov;86(11):1197-204. doi: 10.1007/s00109-008-0380-9. Epub 2008 Jun 24. Citation on PubMed
  • Ogasawara M, Nishino I. A review of major causative genes in congenital myopathies. J Hum Genet. 2023 Mar;68(3):215-225. doi: 10.1038/s10038-022-01045-w. Epub 2022 Jun 7. Citation on PubMed
  • Ross JE, Flowers M, McNulty S, Patel M, Yang H, Palus B, Abdelmoneim Elnagheeb M, Eng L, Owens E, Beggs AH, Bertini E, D'Amico A, Donkervoort S, Dowling J, Fattori F, Ferreiro A, Genetti CA, Gonorazky H, Lek M, Lindy A, Medne L, Muntoni F, Pajusalu S, Pelin K, Rendu J, Sarkozy A, Vatta M, Winder T, Yoon G, Bonnemann CG, Ceyhan-Birsoy O. Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel. J Neuromuscul Dis. 2025 Nov;12(6):778-792. doi: 10.1177/22143602251339369. Epub 2025 Jun 10. Citation on PubMed
  • Schroder JM, Durling H, Laing N. Actin myopathy with nemaline bodies, intranuclear rods, and a heterozygous mutation in ACTA1 (Asp154Asn). Acta Neuropathol. 2004 Sep;108(3):250-6. doi: 10.1007/s00401-004-0888-1. Epub 2004 Jun 24. Citation on PubMed
  • Sparrow JC, Nowak KJ, Durling HJ, Beggs AH, Wallgren-Pettersson C, Romero N, Nonaka I, Laing NG. Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul Disord. 2003 Sep;13(7-8):519-31. doi: 10.1016/s0960-8966(03)00101-9. Citation on PubMed
  • Wallefeld W, Krause S, Nowak KJ, Dye D, Horvath R, Molnar Z, Szabo M, Hashimoto K, Reina C, De Carlos J, Rosell J, Cabello A, Navarro C, Nishino I, Lochmuller H, Laing NG. Severe nemaline myopathy caused by mutations of the stop codon of the skeletal muscle alpha actin gene (ACTA1). Neuromuscul Disord. 2006 Oct;16(9-10):541-7. doi: 10.1016/j.nmd.2006.07.018. Epub 2006 Sep 1. Citation on PubMed

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