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Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation.

Haywood NJ, Wolny M, Rogers B, Trinh CH, Shuping Y, Edwards TA, Peckham M
Biochem J 473 2485-93 (2016)
Related entries: 5a36, 5a38, 5a4b

Cited: 27 times
EuropePMC logo PMID: 27287556

Abstract

α-Actinin-2 (ACTN2) is the only muscle isoform of α-actinin expressed in cardiac muscle. Mutations in this protein have been implicated in mild to moderate forms of hypertrophic cardiomyopathy (HCM). We have investigated the effects of two mutations identified from HCM patients, A119T and G111V, on the secondary and tertiary structure of a purified actin binding domain (ABD) of ACTN2 by circular dichroism and X-ray crystallography, and show small but distinct changes for both mutations. We also find that both mutants have reduced F-actin binding affinity, although the differences are not significant. The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localization and dynamic behaviour. Overall, these two mutations have small effects on structure, function and behaviour, which may contribute to a mild phenotype for this disease.

Articles - 5a37 mentioned but not cited (2)

  1. Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation. Haywood NJ, Wolny M, Rogers B, Trinh CH, Shuping Y, Edwards TA, Peckham M. Biochem J 473 2485-2493 (2016)
  2. Tissue Extract from Brittle Star Undergoing Arm Regeneration Promotes Wound Healing in Rat. Afshar A, Khoradmehr A, Nowzari F, Baghban N, Zare M, Najafi M, Keshavarzi SZ, Zendehboudi F, Mohebbi G, Barmak A, Mohajer F, Basouli N, Keshtkar M, Iraji A, Sari Aslani F, Irajie C, Nabipour I, Mahmudpour M, Tanideh N, Tamadon A. Mar Drugs 21 381 (2023)


Reviews citing this publication (7)

  1. The Role of Z-disc Proteins in Myopathy and Cardiomyopathy. Wadmore K, Azad AJ, Gehmlich K. Int J Mol Sci 22 3058 (2021)
  2. Mutation update for the ACTN2 gene. Ranta-Aho J, Olive M, Vandroux M, Roticiani G, Dominguez C, Johari M, Torella A, Böhm J, Turon J, Nigro V, Hackman P, Laporte J, Udd B, Savarese M. Hum Mutat 43 1745-1756 (2022)
  3. Actin-associated proteins and cardiomyopathy-the 'unknown' beyond troponin and tropomyosin. Ehler E. Biophys Rev 10 1121-1128 (2018)
  4. Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies. Brodehl A, Ebbinghaus H, Deutsch MA, Gummert J, Gärtner A, Ratnavadivel S, Milting H. Int J Mol Sci 20 (2019)
  5. Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies. Pecorari I, Mestroni L, Sbaizero O. Int J Mol Sci 21 (2020)
  6. Structural Characteristics, Binding Partners and Related Diseases of the Calponin Homology (CH) Domain. Yin LM, Schnoor M, Jun CD. Front Cell Dev Biol 8 342 (2020)
  7. Structural and signaling proteins in the Z-disk and their role in cardiomyopathies. Noureddine M, Gehmlich K. Front Physiol 14 1143858 (2023)

Articles citing this publication (18)

  1. ACTN2 mutations cause "Multiple structured Core Disease" (MsCD). Lornage X, Romero NB, Grosgogeat CA, Malfatti E, Donkervoort S, Marchetti MM, Neuhaus SB, Foley AR, Labasse C, Schneider R, Carlier RY, Chao KR, Medne L, Deleuze JF, Orlikowski D, Bönnemann CG, Gupta VA, Fardeau M, Böhm J, Laporte J, Laporte J. Acta Neuropathol 137 501-519 (2019)
  2. Affimer proteins for F-actin: novel affinity reagents that label F-actin in live and fixed cells. Lopata A, Hughes R, Tiede C, Heissler SM, Sellers JR, Knight PJ, Tomlinson D, Peckham M. Sci Rep 8 6572 (2018)
  3. Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations. Savarese M, Palmio J, Poza JJ, Weinberg J, Olive M, Cobo AM, Vihola A, Jonson PH, Sarparanta J, García-Bragado F, Urtizberea JA, Hackman P, Udd B. Ann Neurol 85 899-906 (2019)
  4. Molecular basis of F-actin regulation and sarcomere assembly via myotilin. Kostan J, Pavšič M, Puž V, Schwarz TC, Drepper F, Molt S, Graewert MA, Schreiner C, Sajko S, van der Ven PFM, Onipe A, Svergun DI, Warscheid B, Konrat R, Fürst DO, Lenarčič B, Djinović-Carugo K. PLoS Biol 19 e3001148 (2021)
  5. Case Reports Case Report: Novel Likely Pathogenic ACTN2 Variant Causing Heterogeneous Phenotype in a Korean Family With Left Ventricular Non-compaction. Park J, Cho YG, Park HW, Cho JS. Front Pediatr 9 609389 (2021)
  6. Disease modeling of a mutation in α-actinin 2 guides clinical therapy in hypertrophic cardiomyopathy. Prondzynski M, Lemoine MD, Zech AT, Horváth A, Di Mauro V, Koivumäki JT, Kresin N, Busch J, Krause T, Krämer E, Schlossarek S, Spohn M, Friedrich FW, Münch J, Laufer SD, Redwood C, Volk AE, Hansen A, Mearini G, Catalucci D, Meyer C, Christ T, Patten M, Eschenhagen T, Carrier L. EMBO Mol Med 11 e11115 (2019)
  7. Identification of key candidate genes and pathways revealing the protective effect of liraglutide on diabetic cardiac muscle by integrated bioinformatics analysis. Dong Y, Yan S, Li GY, Wang MN, Leng L, Li Q. Ann Transl Med 8 181 (2020)
  8. Molecular autopsy and clinical family screening in a case of sudden cardiac death reveals ACTN2 mutation related to hypertrophic/dilated cardiomyopathy and a novel LZTR1 variant associated with Noonan syndrome. Kraoua L, Jaouadi H, Allouche M, Achour A, Kaouther H, Ahmed HB, Chaker L, Maazoul F, Ouarda F, Zaffran S, M'rad R. Mol Genet Genomic Med 10 e1954 (2022)
  9. Sarcomeric and nonmuscle α-actinin isoforms exhibit differential dynamics at skeletal muscle Z-lines. Hsu CP, Moghadaszadeh B, Hartwig JH, Beggs AH. Cytoskeleton (Hoboken) 75 213-228 (2018)
  10. Case Reports Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia. Fan LL, Huang H, Jin JY, Li JJ, Chen YQ, Xiang R. Cytogenet Genome Res 157 148-152 (2019)
  11. miRNA-mRNA crosstalk in myocardial ischemia induced by calcified aortic valve stenosis. Duan C, Cao Z, Tang F, Jian Z, Liang C, Liu H, Xiao Y, Liu L, Ma R. Aging (Albany NY) 11 448-466 (2019)
  12. ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes. Zech ATL, Prondzynski M, Singh SR, Pietsch N, Orthey E, Alizoti E, Busch J, Madsen A, Behrens CS, Meyer-Jens M, Mearini G, Lemoine MD, Krämer E, Mosqueira D, Virdi S, Indenbirken D, Depke M, Salazar MG, Völker U, Braren I, Pu WT, Eschenhagen T, Hammer E, Schlossarek S, Carrier L. Cells 11 2745 (2022)
  13. Cullin-3 dependent deregulation of ACTN1 represents a new pathogenic mechanism in nemaline myopathy. Blondelle J, Tallapaka K, Seto JT, Ghassemian M, Clark M, Laitila JM, Bournazos A, Singer JD, Lange S. JCI Insight 5 (2019)
  14. Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2. Broadway-Stringer S, Jiang H, Wadmore K, Hooper C, Douglas G, Steeples V, Azad AJ, Singer E, Reyat JS, Galatik F, Ehler E, Bennett P, Kalisch-Smith JI, Sparrow DB, Davies B, Djinovic-Carugo K, Gautel M, Watkins H, Gehmlich K. Cells 12 721 (2023)
  15. Panorama of the distal myopathies. Savarese M, Sarparanta J, Vihola A, Jonson PH, Johari M, Rusanen S, Hackman P, Udd B. Acta Myol 39 245-265 (2020)
  16. Structural and functional characterization of a plant alpha-actinin. Persson K, Backman L. FEBS Open Bio (2021)
  17. Transcriptome Profiling across Five Tissues of Giant Panda. Li F, Wang C, Xu Z, Li M, Deng L, Wei M, Zhang H, Wu K, Ning R, Li D, Yang M, Zhang M, Ni Q, Zeng B, Li D, Li Y. Biomed Res Int 2020 3852586 (2020)
  18. Whole exome sequencing with a focus on cardiac disease-associated genes in families of sudden unexplained deaths in Yunnan, southwest of China. Wei SJ, Du JL, Wang YB, Qu PF, Ma L, Sun ZC, Tang X, Liu K, Xi YM, Nie SJ, Jia PL, Long W, Qu YQ, Li YH, Lei PP. BMC Genomics 24 57 (2023)


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