Research progress on the expression of the RBM20 gene in dilated cardiomyopathy

LIN Xin; ZHOU Yan

doi:10.7499/j.issn.1008-8830.2306087

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Chinese Journal of Contemporary Pediatrics ›› 2023, Vol. 25 ›› Issue (10) : 1084-1088. DOI: 10.7499/j.issn.1008-8830.2306087

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Research progress on the expression of the RBM20 gene in dilated cardiomyopathy

LIN Xin, ZHOU Yan

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Abstract

Dilated cardiomyopathy (DCM) is a significant contributor to heart failure and can lead to life-threatening cardiovascular events at any stage. RNA-binding motif protein 20 (RBM20) gene mutation is known to be one of the causes of DCM. This mutation exhibits familial aggregation and is associated with arrhythmias, increasing the risk of sudden and early death. This article delves into the characteristics of the RBM20 gene, highlighting its role in regulating alternative splicing of the TTN gene and calcium/calmodulin-dependent protein kinase type II gene. Furthermore, the article provides a summary of treatment options available for DCM caused by RBM20 gene mutations, aiming to enhance clinicians' understanding of the RBM20 gene and provide new ideas for precision medicine treatment.

Key words

Dilated cardiomyopathy / RBM20 gene / Alternative splicing

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LIN Xin, ZHOU Yan. Research progress on the expression of the RBM20 gene in dilated cardiomyopathy[J]. Chinese Journal of Contemporary Pediatrics. 2023, 25(10): 1084-1088 https://doi.org/10.7499/j.issn.1008-8830.2306087

References

1 Brodehl A, Gaertner-Rommel A, Milting H. FLNC (filamin-C): a new(er) player in the field of genetic cardiomyopathies[J]. Circ Cardiovasc Genet, 2017, 10(6): e001959. PMID: 29212901. DOI: 10.1161/CIRCGENETICS.117.001959.
2 Zahr HC, Jaalouk DE. Exploring the crosstalk between LMNA and splicing machinery gene mutations in dilated cardiomyopathy[J]. Front Genet, 2018, 9: 231. PMID: 30050558. PMCID: PMC6052891. DOI: 10.3389/fgene.2018.00231.
3 Brauch KM, Karst ML, Herron KJ, et al. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy[J]. J Am Coll Cardiol, 2009, 54(10): 930-941. PMID: 19712804. PMCID: PMC2782634. DOI: 10.1016/j.jacc.2009.05.038.
4 Robles-Mezcua A, Rodríguez-Miranda L, Morcillo-Hidalgo L, et al. Phenotype and progression among patients with dilated cardiomyopathy and RBM20 mutations[J]. Eur J Med Genet, 2021, 64(9): 104278. PMID: 34174465. DOI: 10.1016/j.ejmg.2021.104278.
5 李雪银, 李广平. 家族性扩张型心肌病基因突变与精准医学[J]. 中华心力衰竭和心肌病杂志（中英文）, 2019, 3(4): 231-234. DOI: 10.3760/cma.j.issn.2096-3076.2019.04.009.
6 Li M, Xia S, Xu L, et al. Genetic analysis using targeted next-generation sequencing of sporadic Chinese patients with idiopathic dilated cardiomyopathy[J]. J Transl Med, 2021, 19(1): 189. PMID: 33941202. PMCID: PMC8091742. DOI: 10.1186/s12967-021-02832-3.
7 Gaertner A, Klauke B, Brodehl A, et al. RBM20 mutations in left ventricular non-compaction cardiomyopathy[J]. Pediatr Investig, 2020, 4(1): 61-63. PMID: 32851345. PMCID: PMC7331358. DOI: 10.1002/ped4.12184.
8 Liatakis I, Prappa E, Gouziouta A, et al. RBM20 mutation and ventricular arrhythmias in a young patient with dilated cardiomyopathy: a case report[J]. Am J Cardiovasc Dis, 2021, 11(3): 398-403. PMID: 34322310. PMCID: PMC8303033.
9 彭昌, 徐合平, 王世远. RBM20基因新发错义突变致家族性儿童扩张性心肌病1例报告[J]. 临床儿科杂志, 2018, 36(12): 912-915. DOI: 10.3969/j.issn.1000-3606.2018.12.007.
10 Maatz H, Jens M, Liss M, et al. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing[J]. J Clin Invest, 2014, 124(8): 3419-3430. PMID: 24960161. PMCID: PMC4109538. DOI: 10.1172/JCI74523.
11 Guo W, Schafer S, Greaser ML, et al. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing[J]. Nat Med, 2012, 18(5): 766-773. PMID: 22466703. PMCID: PMC3569865. DOI: 10.1038/nm.2693.
12 Watanabe T, Kimura A, Kuroyanagi H. Alternative splicing regulator RBM20 and cardiomyopathy[J]. Front Mol Biosci, 2018, 5: 105. PMID: 30547036. PMCID: PMC6279932. DOI: 10.3389/fmolb.2018.00105.
13 Koelemen J, Gotthardt M, Steinmetz LM, et al. RBM20-related cardiomyopathy: current understanding and future options[J]. J Clin Med, 2021, 10(18): 4101. PMID: 34575212. PMCID: PMC8468976. DOI: 10.3390/jcm10184101.
14 Nishiyama T, Zhang Y, Cui M, et al. Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy[J]. Sci Transl Med, 2022, 14(672): eade1633. PMID: 36417486. PMCID: PMC10088465. DOI: 10.1126/scitranslmed.ade1633.
15 Gaertner A, Bloebaum J, Brodehl A, et al. The combined human genotype of truncating TTN and RBM20 mutations is associated with severe and early onset of dilated cardiomyopathy[J]. Genes (Basel), 2021, 12(6): 883. PMID: 34201072. PMCID: PMC8228627. DOI: 10.3390/genes12060883.
16 Gaertner A, Klauke B, Felski E, et al. Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20[J]. Hum Mutat, 2020, 41(11): 1931-1943. PMID: 32840935. DOI: 10.1002/humu.24096.
17 Dauksaite V, Gotthardt M. Molecular basis of titin exon exclusion by RBM20 and the novel titin splice regulator PTB4[J]. Nucleic Acids Res, 2018, 46(10): 5227-5238. PMID: 29518215. PMCID: PMC6007684. DOI: 10.1093/nar/gky165.
18 Yamamoto T, Sano R, Miura A, et al. I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy[J]. J Mol Med (Berl), 2022, 100(12): 1741-1754. PMID: 36198914. PMCID: PMC9691496. DOI: 10.1007/s00109-022-02262-8.
19 Zhang Y, Gregorich ZR, Wang Y, et al. Disruption of the nuclear localization signal in RBM20 is causative in dilated cardiomyopathy[J]. JCI insight, 2023, 8(13): e170001. PMID: 37219949. PMCID: PMC10371347. DOI: 10.1172/jci.insight.170001.
20 Murayama R, Kimura-Asami M, Togo-Ohno M, et al. Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-binding motif protein 20 (RBM20) through nuclear localization[J]. Sci Rep, 2018, 8(1): 8970. PMID: 29895960. PMCID: PMC5997748. DOI: 10.1038/s41598-018-26624-w.
21 Sun M, Jin Y, Zhang Y, et al. SR protein kinases regulate the splicing of cardiomyopathy-relevant genes via phosphorylation of the RSRSP stretch in RBM20[J]. Genes (Basel), 2022, 13(9): 1526. PMID: 36140694. PMCID: PMC9498672. DOI: 10.3390/genes13091526.
22 Ihara K, Sasano T, Hiraoka Y, et al. A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice[J]. Sci Rep, 2020, 10(1): 17894. PMID: 33110103. PMCID: PMC7591520. DOI: 10.1038/s41598-020-74800-8.
23 Zhang Y, Wang C, Sun M, et al. RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis[J]. FASEB J, 2022, 36(5): e22302. PMID: 35394688. PMCID: PMC9233413. DOI: 10.1096/fj.202101811RR.
24 Upadhyay SK, Mackereth CD. Structural basis of UCUU RNA motif recognition by splicing factor RBM20[J]. Nucleic Acids Res, 2020, 48(8): 4538-4550. PMID: 32187365. PMCID: PMC7192616. DOI: 10.1093/nar/gkaa168.
25 Fenix AM, Miyaoka Y, Bertero A, et al. Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies[J]. Nat Commun, 2021, 12(1): 6324. PMID: 34732726. PMCID: PMC8566601. DOI: 10.1038/s41467-021-26623-y.
26 郑奎, 娄美娜. TTN基因突变致儿童扩张型心肌病的研究进展[J]. 中国当代儿科杂志, 2023, 25(2): 217-222. PMID: 36854701. PMCID: PMC9979384. DOI: 10.7499/j.issn.1008-8830.2208163.
27 Lennermann D, Backs J, van den Hoogenhof MMG. New insights in RBM20 cardiomyopathy[J]. Curr Heart Fail Rep, 2020, 17(5): 234-246. PMID: 32789749. PMCID: PMC7495990. DOI: 10.1007/s11897-020-00475-x.
28 Domínguez F, Lalaguna L, Martínez-Martín I, et al. Titin missense variants as a cause of familial dilated cardiomyopathy[J]. Circulation, 2023, 147(22): 1711-1713. PMID: 37253077. DOI: 10.1161/CIRCULATIONAHA.122.062833.
29 Li N, Hang W, Shu H, et al. RBM20, a therapeutic target to alleviate myocardial stiffness via titin isoforms switching in HFpEF[J]. Front Cardiovasc Med, 2022, 9: 928244. PMID: 35783855. PMCID: PMC9243441. DOI: 10.3389/fcvm.2022.928244.
30 van den Hoogenhof MMG, Beqqali A, Amin AS, et al. RBM20 mutations induce an arrhythmogenic dilated cardiomyopathy related to disturbed calcium handling[J]. Circulation, 2018, 138(13): 1330-1342. PMID: 29650543. DOI: 10.1161/CIRCULATIONAHA.117.031947.
31 Long C, Liu X, Xiong Q, et al. Sex differences in dilated cardiomyopathy prognosis[J]. Int Heart J, 2022, 63(1): 36-42. PMID: 35095074. DOI: 10.1536/ihj.20-448.
32 Hey TM, Rasmussen TB, Madsen T, et al. Pathogenic RBM20-variants are associated with a severe disease expression in male patients with dilated cardiomyopathy[J]. Circ Heart Fail, 2019, 12(3): e005700. PMID: 30871348. DOI: 10.1161/CIRCHEARTFAILURE.118.005700.
33 Lennermann DC, Pepin ME, Grosch M, et al. Deep phenotyping of two preclinical mouse models and a cohort of RBM20 mutation carriers reveals no sex-dependent disease severity in RBM20 cardiomyopathy[J]. Am J Physiol Heart Circ Physiol, 2022, 323(6): H1296-H1310. PMID: 36367695. DOI: 10.1152/ajpheart.00328.2022.
34 Liss M, Radke MH, Eckhard J, et al. Drug discovery with an RBM20 dependent titin splice reporter identifies cardenolides as lead structures to improve cardiac filling[J]. PLoS One, 2018, 13(6): e0198492. PMID: 29889873. PMCID: PMC5995442. DOI: 10.1371/journal.pone.0198492.
35 Briganti F, Sun H, Wei W, et al. iPSC modeling of RBM20-deficient DCM identifies upregulation of RBM20 as a therapeutic strategy[J]. Cell Rep, 2020, 32(10): 108117. PMID: 32905764. PMCID: PMC8168789. DOI: 10.1016/j.celrep.2020.108117.