1.SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy
Boeckel JES-NIELS ; M?bius-Winkler MAXIMILIAN ; Müller MARION ; Rebs SABINE ; Eger NICOLE ; Schoppe LAURA ; Tappu REWATI ; E.Kokot KAROLINE ; M.Kneuer JASMIN ; Gaul SUSANNE ; M.Bordalo DIANA ; Lai ALAN ; Haas JAN ; Ghanbari MAHSA ; Drewe-Boss PHILIPP ; Liss MARTIN ; A.Katus HUGO ; Ohler UWE ; Gotthardt MICHAEL ; Laufs ULRICH ; Streckfuss-B?meke KATRIN ; Meder BENJAMIN
Genomics, Proteomics & Bioinformatics 2022;20(1):129-146
Alternative mRNA splicing is a fundamental process to increase the versatility of the gen-ome.In humans,cardiac mRNA splicing is involved in the pathophysiology of heart failure.Mutations in the splicing factor RNA binding motif protein 20(RBM20)cause severe forms of cardiomyopathy.To identify novel cardiomyopathy-associated splicing factors,RNA-seq and tissue-enrichment anal-yses were performed,which identified up-regulated expression of Sam68-Like mammalian protein 2(SLM2)in the left ventricle of dilated cardiomyopathy(DCM)patients.In the human heart,SLM2 binds to important transcripts of sarcomere constituents,such as those encoding myosin light chain 2(MYL2),troponin I3(TNNI3),troponin T2(TNNT2),tropomyosin 1/2(TPM1/2),and titin(TTN).Mechanistically,SLM2 mediates intron retention,prevents exon exclusion,and thereby medi-ates alternative splicing of the mRNA regions encoding the variable proline-,glutamate-,valine-,and lysine-rich(PEVK)domain and another part of the I-band region of titin.In summary,SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding to and processing the mRNAs of essential cardiac constituents such as titin.
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