| ACTG1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | ACTG1, ACT, ACTG, BRWS2, DFNA20, DFNA26, HEL-176, actin gamma 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:102560;MGI:87906;HomoloGene:74402;GeneCards:ACTG1;OMA:ACTG1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Actin, cytoplasmic 2, orgamma-actin is aprotein that in humans is encoded by theACTG1gene.[5] Gamma-actin is widely expressed in cellularcytoskeletons of many tissues; in adultstriated muscle cells, gamma-actin is localized toZ-discs andcostamere structures, which are responsible for force transduction and transmission in muscle cells. Mutations inACTG1 have been associated withnonsyndromic hearing loss and Baraitser-Winter syndrome, as well as susceptibility of adolescent patients tovincristine toxicity.
Human gamma-actin is 41.8 kDa in molecular weight and 375amino acids in length.[6] Actins are highly conserved proteins that are involved in various types of cell motility, and maintenance of the cytoskeleton. Invertebrates, three main groups of actinparalogs, alpha, beta, and gamma, have been identified.[7]
The alpha actins are found in muscle tissues and are a major constituent of thesarcomere contractile apparatus. The beta and gamma actins co-exist in most cell types as components of thecytoskeleton, and as mediators of internal cell motility. Actin, gamma 1, encoded by this gene, is found in non-muscle cells in thecytoplasm, and in muscle cells atcostamere structures, or transverse points ofcell-cell adhesion that run perpendicular to the long axis ofmyocytes.[8][9][10]
Inmyocytes,sarcomeres adhere to thesarcolemma viacostameres, which align atZ-discs andM-lines.[11] The two primarycytoskeletal components ofcostameres aredesminintermediate filaments and gamma-actin microfilaments.[12] It has been shown that gamma-actin interacting with anothercostamericproteindystrophin is critical forcostameres forming mechanically strong links between thecytoskeleton and thesarcolemmal membrane.[13][14] Additional studies have shown that gamma-actin colocalizes withalpha-actinin andGFP-labeled gamma actin localized toZ-discs, whereasGFP-alpha-actin localized to pointed ends ofthin filaments, indicating that gamma actin specifically localizes toZ-discs instriated muscle cells.[15][16][17]
During development ofmyocytes, gamma actin is thought to play a role in the organization and assembly of developingsarcomeres, evidenced in part by its early colocalization withalpha-actinin.[18] Gamma-actin is eventually replaced bysarcomericalpha-actin isoforms,[19][20][21] with low levels of gamma-actin persisting in adultmyocytes which associate withZ-disc andcostamere domains.[15][22][23]
Insights into the function of gamma-actin in muscle have come from studies employing transgenesis. In askeletal muscle-specific knockout of gamma-actin in mice, these animals showed no detectable abnormalities in development; however, knockout mice showed muscle weakness and fibernecrosis, along with decreasedisometric twitch force, disrupted intrafibrillar and interfibrillar connections amongmyocytes, andmyopathy.[24]
An autosomal dominant mutation inACTG1 in the DFNA20/26 locus at 17q25-qter was identified in patients with hearing loss. AThr278Ile mutation was identified in helix 9 of gamma-actinprotein, which is predicted to alterprotein structure. This study identified the first disease causing mutation in gamma-actin and underlies the importance of gamma-actin as structural elements of the inner ear hair cells.[25] Since then, otherACTG1 mutations have been linked tononsyndromic hearing loss, includingMet305Thr.[26]
A missense mutation inACTG1 atSer155Phe has also been identified in patients withBaraitser-Winter syndrome, which is a developmental disorder characterized by congenitalptosis, excessively-arched eyebrows,hypertelorism, ocularcolobomata,lissencephaly, short stature, seizures and hearing loss.[27][28]
Differential expression ofACTG1mRNA was also identified in patients withSporadic Amyotrophic Lateral Sclerosis, a devastating disease with unknown causality, using a sophisticatedbioinformatics approach employingAffymetrix long-oligonucleotide BaFL methods.[29]
Single nucleotide polymorphisms inACTG1 have been associated withvincristine toxicity, which is part of the standard treatment regimen for childhoodacute lymphoblastic leukemia.Neurotoxicity was more frequent in patients that wereACTG1Gly310Ala mutation carriers, suggesting that this may play a role in patient outcomes fromvincristine treatment.[30]
ACTG1 has been shown tointeract with:
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