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Identification of Novel Mutations in RBM20 in Patients with Dilated Cardiomyopathy


To date, the genetic cause of the majority of dilated cardiomyopathy (DCM) cases remains unresolved despite the fact that mutations in more than 30 genes have been shown to be disease causing or disease associated [1, 2].
Most of the genes in which mutations cause DCM, encode sarcomeric proteins involved in contraction, or cytoskeletal proteins important for cell structure or force transduction.
Brauch et al. previously identified a novel non-sarcomeric, non-cytoskeletal gene underlying DCM [3]. Using genetic linkage analysis, the authors first mapped the disease locus to chromosome 10q25, then screened positional candidate genes within this locus and identified missense mutations in exon 9 of RNA-binding motif protein 20 (RBM20), in each of the linked families as well as in multiple probands.
Where available, family members of these probands were tested, revealing further evidence that RBM20 mutations are associated with DCM and suggesting the pathogenicity of these mutations. Ultimately, heterozygous missense mutations in exon 9 of RBM20 were found in 3% of all DCM cases tested, and in over 13% of those with a history of sudden death [3].

RBM20 is predominantly expressed in the heart according to the gene expression omnibus (GEO) database. A “Conserved Domain Data”- base search of the translated reference RBM20 cDNA indicated homology to an RNA Recognition Motif 1 Superfamily domain (RRM-1) spanning exons 6 and 7 and a arginin /serine (RS)-rich [4] domain (in exon 9) prototypical of spliceosome proteins that regulate alternative pre-messenger RNA splicing [5].

Li et al recently reported the discovery of novel mutations in RBM20 in patients with dilated cardiomyopathy [6].
To further evaluate the role of RBM20 in DCM pathogenesis and the DCM clinical characteristics caused by RBM20 mutations, the authors genetically screened a cohort of 312 DCM probands, and their family members when a mutation was identified.
While Brauch et al. screened all exons of RBM20, Li et al. focused their study on the most conserved regions of RBM20. Bidirectional DNA sequencing was conducted for the region of RBM20 showing strong conservation across species, including exon 6 through exon 9. Both the RNA recognition motif region 1 (RRM-1) and the arginine/serine (RS) rich domains are also located within this region.

Six unique missense mutations were found in six unrelated probands, four of which were novel (V535I, R634W, R636C, and R716Q) and two were previously described by Brauch et al. (R634Q and R636H) [3].
These variants were predicted to alter highly conserved amino acids, none of which were present in dbSNP or 450 Caucasian control DNAs.

Consistent with Brauch et al., four of the six mutations were located in the same mutation hotspot in the RS-rich region in exon 9 and modified two amino acids (R634 and R636). The two other novel mutations (V535I and R716Q) were found in domains outside of the hotspot region. V535I was found in exon 6 in the strictly conserved RRM-1. R716Q was located in exon 9 approximately 60 residues downstream of the RS-rich region (residues 632–654). All available DNA specimens from family members of the probands with RBM20 mutations were also sequenced for the family mutation. Seventeen family members from three unrelated probands tested positive for the family mutations.

These RBM20 mutations were clinically manifested as mild-to-severe DCM, including heart failure, or the need for heart transplantation or an implantable cardiac defibrillator (ICD). The average age of DCM onset for the RBM20 mutation carriers was 37.1 years, and the mean LVEF was 31%. Six mutation carriers also had an ICD or pacemaker implanted, and several subjects had supraventricular and/or ventricular arrhythmias, suggesting that RBM20 mutations in addition to disturbing cardiac contraction may also adversely impact cardiac conduction and rhythm. No patient who carried an RBM20 mutation had left ventricular hypertrophy by echocardiography, with left ventricular septal and posterior wall measurements within normal limits .Two RBM20 mutations (V535I, and R634Q) had sporadic DCM, while the other four (R634W, R636C, R636H, and R716Q) had familial DCM consistent with autosomal dominant inheritance.

Myocardial Disease


The function of RBM20 and thereby the mechanism through which RBM20 mutations may cause DCM remains to be elucidated. The functional relevance of the RRM-1, the RS and the U1 zinc-finger domain can be readily deducted from their strict conservation among vertebrates. The RRM-1 domain is thought to bind the target transcript precursor and regulate splicing [4, 7]. Therefore one could speculate that the RBM20 mutation V535I residing in the highly conserved RRM-1 region may interfere with its RNA-binding capacity.
Four RBM20 mutations (R634Q, R634C, R636C, and R636H) altered two highly conserved arginine residues in its RS-rich region. Since the RS-rich domain is predicted to be involved in protein–protein interaction [4, 7], those mutations may affect the ability of RBM20 to interact with other spliceosome proteins, thus disrupting the normal RNA splicing process.
A pathogenic link between genetic disruption of alternative splicing-regulating RS proteins of the spliceosome and DCM has been established earlier in mouse models [8, 9].
Furthermore, the general alternative splicing factor/splicing factor 2 (ASF/SF2) has been directly implicated in the transition between fetal and adult gene programs within the heart [9].
Whether RBM20 acts in a similar manner remains to be investigated, but it will be interesting to define the transcripts of which splicing is regulated by RBM20. This information will elucidate the downstream pathways involved in the etiology of DCM and may eventually help to explore possible therapies.


Clinical implications and prospects

The results described in Li et al., confirm that RBM20 mutations should be considered in familial DCM. It further corroborates that RBM20 mutations are frequently associated with a clinically aggressive form of DCM. This includes severe heart failure, arrhythmia, and the need for cardiac transplantation at ages younger than for sporadic DCM, suggesting that this may be an important cause of familial DCM.  This independent confirmation after the initial report in 2009 by Brauch et al.  [3] more firmly suggests RBM20 as a novel candidate gene to the list of DCM associated genes. However, its precise frequency and pathophysiological role still needs to be determined. Most importantly, close examination of the described families reveals that penetrance may be variable and in the only large pedigree described by Li et al, variations in other DCM related genes were found as well. A robust pathophysiological role for RBM20 in DCM therefore still needs to be established,

Given the suggested malignancy of RBM20 mutations, finding mutations would suggest a closer clinical follow up, careful attention to coexistent modifiable risk factors, and earlier application of therapies proven to inhibit the process of heart failure and decrease the risk of sudden death.




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  2. Karkkainen, S. and K. Peuhkurinen, Genetics of dilated cardiomyopathy. Ann Med, 2007. 39(2): p. 91-107.
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Notes to editor

Duanxiang Li, M.D., M.S., Ana Morales , M.S., C.G.C., Jorge Gonzalez-Quintana , B.S. , Nadine Norton , Ph.D., Jill D. Siegfried , M.S., C.G.C., Mark Hofmeyer, M.D., and
Ray E. Hershberger, M.D.
Clinical and translational science 2010; Volume 3: 90–97.

Presented by Dr. Abdelaziz Beqqali and Prof. Dr. Yigal Pinto
Heart Failure Research Center, University of Amsterdam,
The Netherlands.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.