The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy.

Anna Gaertner,Uwe Schulz,Michiel Morshuis,Ralph Knoell,Jan Gummert,Katharina Sielemann,Astrid Kassner,Jens Tiesmeier,Henrik Fox,Hendrik Milting,Julia Bloebaum,Andreas Brodehl,Baerbel Klauke

doi:10.3390/genes12060883

Abstract

A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN (TTNtv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are also known to be associated with severe cardiomyopathies. TTN is one of the major RBM20 splicing targets. Most of the pathogenic RBM20 mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant RBM20. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic TTN and RBM20 mutations. We show that the splicing of RBM20 target genes is affected in the mutation carrier. Furthermore, we reveal RBM20 haploinsufficiency presumably caused by the frameshift mutation in RBM20.

Highlights

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure (HF), with an estimated prevalence of 1 in 200–500 people and the most common indication for heart transplantation (HTx) [1–3]
We have identified a combination of truncating RNA binding motif protein 20 (RBM20) (NM_001134363) and TTN
Mutations in RBM20 have been associated with dilated cardiomyopathy (DCM) already in 2009 [9] and missplicing of several important cardiac genes like TTN was recognized as the potential pathomechanism induced by pathogenic RBM20 mutations [8,13]

Summary

Introduction

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure (HF), with an estimated prevalence of 1 in 200–500 people and the most common indication for heart transplantation (HTx) [1–3]. DCM is defined by left-ventricular chamber dilatation in combination with systolic dysfunction [4]. RBM20 is a cardiomyopathy-associated gene (MIM #613172), which is predominantly expressed in striated muscle with highest expression in the heart [7–10]. DCM is highly penetrant and clinically aggressive. It is characterized by an early onset and an increased risk for malignant ventricular arrhythmias [11,12]. RNA binding motif protein 20 (RBM20) belongs to the serine and arginine rich (SR) like proteins. It contains domains, which are characteristic for other splicing factors like the ribonucleic acid recognition motif (RRM) and an RS domain, which are highly conserved

Methods

Results

Conclusion