The Clinical Spectrum of Mutations in CAP2

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Aviva Levitas Hanna Krymko Leonel Slanovic Ruti Parvari


Background: Dilated cardiomyopathy leads to contractile dysfunction, progressive heart failure, and excessive risk of sudden cardiac death. We reported a homozygous damaging variation in CAP2 causing dilated cardiomyopathy and supraventricular tachycardia in two cousins of one family. Additional homozygous mutations in CAP2 with clinical presentations were reported.

 Aim: To present the different CAP2 mutations described in patients of various populations with a spectrum of clinical descriptions and possibly correlate the mutations to the clinical findings. This is important for the diagnosing and prognosis of patients with mutations in this gene.

Methods: Clinical evaluation of an additional patient of the family we previously reported. Literature searches of clinical studies of patients affected by mutations in CAP2, animal models for the gene, and the role of CAP2 in the assembly of actin in the thin filaments of the sarcomere.

Results: All patients had dilated cardiomyopathy necessitating heart transplants at a very young age. Two patients with one loss of function mutation presented additionally with structural heart abnormalities. Another loss of function mutation in one patient associated with nemaline myopathy, mild hypotonia, atrophic, and widened scarring. One report did not detail the patient's mutation and presented tricuspid and pulmonary atresia. Animal models of mice and sheep had additional defects not reported in human patients. The pathology is caused by the loss of the function of CAP2 in actin polymerization and in the “α-actin switch” occurring during differentiation and required for the sarcomere structure and function.

Conclusions: The homozygous mutations in CAP2 cause severe Dilated cardiomyopathy. Additional phenotypes may not be seen in all individuals, and the severity of the mutation and disease do not correlate.

Keywords: Dilated cardiomyopathy, CAP2, Loss of function versus reduced function mutation, clinical characteristics

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How to Cite
LEVITAS, Aviva et al. The Clinical Spectrum of Mutations in CAP2. Medical Research Archives, [S.l.], v. 10, n. 11, nov. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 17 june 2024. doi:
Research Articles


1. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. Sep 2013;10(9):531-547.
2. den Boer SL, Lennie van Osch-Gevers M, van Ingen G, et al. Management of children with dilated cardiomyopathy in The Netherlands: Implications of a low early transplantation rate. J Heart Lung Transplant. Jul 2015;34(7):963-969.
3. Kirk R, Naftel D, Hoffman TM, et al. Outcome of pediatric patients with dilated cardiomyopathy listed for transplant: a multi-institutional study. J Heart Lung Transplant. Dec 2009;28(12):1322-1328.
4. Pinto YM, Elliott PM, Arbustini E, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. Jun 14 2016;37(23):1850-1858.
5. Grunig E, Tasman JA, Kucherer H, Franz W, Kubler W, Katus HA. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. Jan 1998;31(1):186-194.
6. McNally EM, Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. The Journal of clinical investigation. Jan 2013;123(1):19-26.
7. Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol. Jul 1999;34(1):181-190.
8. Parvari R, Levitas A. The mutations associated with dilated cardiomyopathy. Biochem Res Int. 2012;2012:639250.
9. Harvey PA, Leinwand LA. The cell biology of disease: cellular mechanisms of cardiomyopathy. J Cell Biol. Aug 08 2011;194(3):355-365.
10. Levitas A, Muhammad E, Harel G, et al. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. Eur J Hum Genet. Oct 2010;18(10):1160-1165.
11. Fowler VM, Dominguez R. Tropomodulins and Leiomodins: Actin Pointed End Caps and Nucleators in Muscles. Biophysical journal. May 9 2017;112(9):1742-1760.
12. Yuen M, Sandaradura SA, Dowling JJ, et al. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. The Journal of clinical investigation. Nov 2014;124(11):4693-4708.
13. Ahrens-Nicklas RC, Pappas CT. Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy. Sci Adv. 2019;5(9):eaax2066.
14. Colpan M, Iwanski J. CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle. Commun Biol. Mar 19 2021;4(1):365.
15. Moriyama K, Yahara I. Human CAP1 is a key factor in the recycling of cofilin and actin for rapid actin turnover. Journal of cell science. Apr 15 2002;115(Pt 8):1591-1601.
16. Chaudhry F, Little K, Talarico L, Quintero-Monzon O, Goode BL. A central role for the WH2 domain of Srv2/CAP in recharging actin monomers to drive actin turnover in vitro and in vivo. Cytoskeleton (Hoboken, N.J.). Feb 2010;67(2):120-133.
17. Kepser LJ, Damar F, De Cicco T, Chaponnier C, Prószyński TJ. CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function. Proc Natl Acad Sci U S A.Apr 23 2019;116(17):8397-8402.
18. Aspit L, Levitas A, Etzion S, et al. CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy. Journal of medical genetics. Apr 2019;56(4):228-235.
19. Gurunathan S, Sebastian J, Baker J, et al. A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods. Am J Med Genet A. Mar 2022;188(3):970-977.
20. Patel R, Peterson R. Cardiomyopathy presenting prenatally with functional tricuspid and pulmonary atresia. Echocardiography Sep 2019;36(9):1779-1782.
21. Cheema H, Bertoli-Avella AM. Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility. NPJ Genom Med 2020;5:44.
22. Field J, Ye DZ, Shinde M, et al. CAP2 in cardiac conduction, sudden cardiac death and eye development. Sci Rep. Nov 30 2015;5:17256.
23. Kosmas K, Eskandarnaz A, Khorsandi AB, et al. CAP2 is a regulator of the actin cytoskeleton and its absence changes infiltration of inflammatory cells and contraction of wounds. Eur J Cell Biol. Jan 2015;94(1):32-45.
24. Peche VS, Holak TA, Burgute BD, et al. Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy. Cell Mol Life Sci. Feb 2013;70(3):527-543.
25. Zhao L, Li F, Yuan L, et al. Expression of ovine CTNNA3 and CAP2 genes and their association with growth traits. Gene. Jan 10 2022;807:145949.
26. Muhammad E, Levitas A, Singh SR, et al. PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction. Human molecular genetics. Dec 20 2015;24(25):7227-7240.
27. Stockigt F, Peche VS, Linhart M, Nickenig G, Noegel AA, Schrickel JW. Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis. Arch Med Sci. Feb 1 2016;12(1):188-198.
28. Iwanski J, Gregorio CC, Colpan M. Redefining actin dynamics of the pointed-end complex in striated muscle. Trends in cell biology. Sep 2021;31(9):708-711.
29. Kotila T, Kogan K, Enkavi G, Guo S, Vattulainen I. Structural basis of actin monomer re-charging by cyclase-associated protein. Nat Commun. May 14 2018;9(1):1892.
30. Kotila T, Wioland H. Mechanism of synergistic actin filament pointed end depolymerization by cyclase-associated protein and cofilin. Nat Commun. Nov 22 2019;10(1):5320.
31. Purde V, Busch F, Kudryashova E. Oligomerization Affects the Ability of Human Cyclase-Associated Proteins 1 and 2 to Promote Actin Severing by Cofilins. Int J Mol Sci. Nov 12 2019;20(22).
32. Fan Z, Zhou S, Garcia C, Fan L, Zhou J. pH-Responsive fluorescent graphene quantum dots for fluorescence-guided cancer surgery and diagnosis. Nanoscale. Apr 13 2017;9(15):4928-4933.
33. Pappas CT, Mayfield RM, Henderson C, et al. Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality. Proceedings of the National Academy of Sciences of the United States of America. Nov 3 2015;112(44):13573-13578.
34. Tolkatchev D, Smith GE, Jr. Leiomodin creates a leaky cap at the pointed end of actin-thin filaments. PLoS Biol. Sep 2020;18(9):e3000848.