7rns

Structural highlights

Disease

ACTS_HUMAN Defects in ACTA1 are the cause of nemaline myopathy type 3 (NEM3) [MIM:161800. A form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-or rod-like structures in muscle fibers on histologic examination. The phenotype at histological level is variable. Some patients present areas devoid of oxidative activity containg (cores) within myofibers. Core lesions are unstructured and poorly circumscribed.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]} Defects in ACTA1 are a cause of myopathy, actin, congenital, with excess of thin myofilaments (MPCETM) [MIM:161800. A congenital muscular disorder characterized at histological level by areas of sarcoplasm devoid of normal myofibrils and mitochondria, and replaced with dense masses of thin filaments. Central cores, rods, ragged red fibers, and necrosis are absent.^[11] Defects in ACTA1 are a cause of congenital myopathy with fiber-type disproportion (CFTD) [MIM:255310; also known as congenital fiber-type disproportion myopathy (CFTDM). CFTD is a genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions.^{[12] [13]}

Function

ACTS_HUMAN Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

References

1. ↑ Nowak KJ, Wattanasirichaigoon D, Goebel HH, Wilce M, Pelin K, Donner K, Jacob RL, Hubner C, Oexle K, Anderson JR, Verity CM, North KN, Iannaccone ST, Muller CR, Nurnberg P, Muntoni F, Sewry C, Hughes I, Sutphen R, Lacson AG, Swoboda KJ, Vigneron J, Wallgren-Pettersson C, Beggs AH, Laing NG. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet. 1999 Oct;23(2):208-12. PMID:10508519 doi:10.1038/13837
2. ↑ Ilkovski B, Cooper ST, Nowak K, Ryan MM, Yang N, Schnell C, Durling HJ, Roddick LG, Wilkinson I, Kornberg AJ, Collins KJ, Wallace G, Gunning P, Hardeman EC, Laing NG, North KN. Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene. Am J Hum Genet. 2001 Jun;68(6):1333-43. Epub 2001 Apr 27. PMID:11333380 doi:S0002-9297(07)61044-1
3. ↑ Jungbluth H, Sewry CA, Brown SC, Nowak KJ, Laing NG, Wallgren-Pettersson C, Pelin K, Manzur AY, Mercuri E, Dubowitz V, Muntoni F. Mild phenotype of nemaline myopathy with sleep hypoventilation due to a mutation in the skeletal muscle alpha-actin (ACTA1) gene. Neuromuscul Disord. 2001 Jan;11(1):35-40. PMID:11166164
4. ↑ 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. PMID:15236405 doi:10.1002/ana.20157
5. ↑ Ilkovski B, Nowak KJ, Domazetovska A, Maxwell AL, Clement S, Davies KE, Laing NG, North KN, Cooper ST. Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms. Hum Mol Genet. 2004 Aug 15;13(16):1727-43. Epub 2004 Jun 15. PMID:15198992 doi:10.1093/hmg/ddh185
6. ↑ Kaindl AM, Ruschendorf F, Krause S, Goebel HH, Koehler K, Becker C, Pongratz D, Muller-Hocker J, Nurnberg P, Stoltenburg-Didinger G, Lochmuller H, Huebner A. Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet. 2004 Nov;41(11):842-8. PMID:15520409 doi:10.1136/jmg.2004.020271
7. ↑ Ohlsson M, Tajsharghi H, Darin N, Kyllerman M, Oldfors A. Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul Disord. 2004 Sep;14(8-9):471-5. PMID:15336687 doi:10.1016/j.nmd.2004.05.016
8. ↑ Hutchinson DO, Charlton A, Laing NG, Ilkovski B, North KN. Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred. Neuromuscul Disord. 2006 Feb;16(2):113-21. Epub 2006 Jan 19. PMID:16427282 doi:10.1016/j.nmd.2005.11.004
9. ↑ D'Amico A, Graziano C, Pacileo G, Petrini S, Nowak KJ, Boldrini R, Jacques A, Feng JJ, Porfirio B, Sewry CA, Santorelli FM, Limongelli G, Bertini E, Laing N, Marston SB. Fatal hypertrophic cardiomyopathy and nemaline myopathy associated with ACTA1 K336E mutation. Neuromuscul Disord. 2006 Oct;16(9-10):548-52. Epub 2006 Sep 1. PMID:16945537 doi:10.1016/j.nmd.2006.07.005
10. ↑ Domazetovska A, Ilkovski B, Kumar V, Valova VA, Vandebrouck A, Hutchinson DO, Robinson PJ, Cooper ST, Sparrow JC, Peckham M, North KN. Intranuclear rod myopathy: molecular pathogenesis and mechanisms of weakness. Ann Neurol. 2007 Dec;62(6):597-608. PMID:17705262 doi:10.1002/ana.21200
11. ↑ Nowak KJ, Wattanasirichaigoon D, Goebel HH, Wilce M, Pelin K, Donner K, Jacob RL, Hubner C, Oexle K, Anderson JR, Verity CM, North KN, Iannaccone ST, Muller CR, Nurnberg P, Muntoni F, Sewry C, Hughes I, Sutphen R, Lacson AG, Swoboda KJ, Vigneron J, Wallgren-Pettersson C, Beggs AH, Laing NG. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet. 1999 Oct;23(2):208-12. PMID:10508519 doi:10.1038/13837
12. ↑ 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. PMID:15468086 doi:10.1002/ana.20260
13. ↑ 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. PMID:17387733 doi:10.1002/ana.21112