扩张型心肌病(DCM)是临床常见的原发性心肌病之一,是造成心脏性猝死的重要原因,至今已报道51个相关致病基因。不同基因导致的DCM亚型具有特异性临床特征与遗传异质性。其中RNA结合基序蛋白20(RNA-binding motif protein 20,RBM20)编码...扩张型心肌病(DCM)是临床常见的原发性心肌病之一,是造成心脏性猝死的重要原因,至今已报道51个相关致病基因。不同基因导致的DCM亚型具有特异性临床特征与遗传异质性。其中RNA结合基序蛋白20(RNA-binding motif protein 20,RBM20)编码心肌特异性mRNA剪接调节因子,是DCM明确致病基因之一。RBM20基因相关DCM具有遗传外显率高、发病年龄早、心脏猝死率高等严重临床表现。其独特的致病分子机制也显示出其作为心力衰竭潜在治疗靶点的可能性。本文将对RBM20相关DCM的发病机理、分子遗传学、临床特征与治疗进行进展性综述,对于DCM亚型的研究强调了基因检测在心血管精准医疗中的重要性。展开更多
Importance:Pathogenic variants in theRBM20 gene are associated with aggressive dilated cardiomyopathy(DCM).Recently,RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy(LVNC).Thus far,o...Importance:Pathogenic variants in theRBM20 gene are associated with aggressive dilated cardiomyopathy(DCM).Recently,RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy(LVNC).Thus far,only five families with LVNC have been reported to carry variants inRBM20.It remains unknown whether the variants inRBM20 associated with DCM can also cause LVNC.Objective:To elucidate the causativeRBM20 variant in two unrelated patients with both LVNC and DCM,and to identify the clinical characteristics associated with variants inRBM20.Methods:Trio whole-exome sequencing(WES)was performed.Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics(ACMG).Results:We identified two distinctde novo variants inRBM20(one per patient)in these two patients with LVNC.Both variants have been reported in patients with DCM,without the LVNC phenotype.Patient 1 was an 11-year-old girl who had DCM,LVNC,and heart failure;the ratio of noncompacted-to-compacted myocardium was 2.7:1.Ade novo heterozygous variant c.1907G>A(p.Arg636His)in exon 9 was identified in this patient.Patient 2 was a 13-year-old boy who had clinical phenotypes identical to those of Patient 1;the ratio of noncompacted-to-compacted myocardium was 3.2:1 in this patient.WES revealed ade novo heterozygous variant c.1909A>G(p.Ser637Gly)in exon 9.Both variants were previously characterized as pathogenic,and our study classified them as pathogenic variants based on the ACMG guidelines.Interpretation:We found that two patients with LVNC had variants inRBM20.Our results extended the clinical spectrum of the twoRBM20 variants and illustrated that the same variant inRBM20 can cause DCM,with or without the LVNC phenotype.展开更多
Serine/arginine (SR)-rich proteins are critical for the regulation of alternative splicing (AS), which generates multiple mRNA isoforms from one gene and provides protein diversity for cell differentiation and tissue ...Serine/arginine (SR)-rich proteins are critical for the regulation of alternative splicing (AS), which generates multiple mRNA isoforms from one gene and provides protein diversity for cell differentiation and tissue development. Genetic evidence suggests that Drosophila genital-specific overexpression of SR-related nuclear matrix protein of 160 kDa (SRml60), an SR prot&n with a PWI RNA-binding motif, causes defective development only in male flies and results in abnonnal male genital structures and abnormal testis. However, the molecular characterization of SRm160 is limited. Using the high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) method in two sex-specific embryonic cell lines, S2 from the male and Kc from the female, we first identified the genome-wide RNA-binding characteristics of SRm160, which preferred binding to the exonic tri-nucleotide repeats GCA and AAC. We then validated this binding through both in vitro gel-shift assay and in vivo splicing of minigenes and found that SRm160 level affects AS of many transcripts. Furthermore, we identified 492 differential binding sites (DBS) of SRm160 varying between the two sex-specific cell lines.Among these DBS-containing genes, splicing factors were highly enriched, including transformer, a key regulator in the sex determination cascade. Analyses of fly mutants demonstrated that the SRm160 level affects AS isoforms of transformer. These findings shed crucial light on SRm160's RNA-binding specificity and regulation of AS in Drosophila sex determination and development.展开更多
文摘扩张型心肌病(DCM)是临床常见的原发性心肌病之一,是造成心脏性猝死的重要原因,至今已报道51个相关致病基因。不同基因导致的DCM亚型具有特异性临床特征与遗传异质性。其中RNA结合基序蛋白20(RNA-binding motif protein 20,RBM20)编码心肌特异性mRNA剪接调节因子,是DCM明确致病基因之一。RBM20基因相关DCM具有遗传外显率高、发病年龄早、心脏猝死率高等严重临床表现。其独特的致病分子机制也显示出其作为心力衰竭潜在治疗靶点的可能性。本文将对RBM20相关DCM的发病机理、分子遗传学、临床特征与治疗进行进展性综述,对于DCM亚型的研究强调了基因检测在心血管精准医疗中的重要性。
文摘Importance:Pathogenic variants in theRBM20 gene are associated with aggressive dilated cardiomyopathy(DCM).Recently,RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy(LVNC).Thus far,only five families with LVNC have been reported to carry variants inRBM20.It remains unknown whether the variants inRBM20 associated with DCM can also cause LVNC.Objective:To elucidate the causativeRBM20 variant in two unrelated patients with both LVNC and DCM,and to identify the clinical characteristics associated with variants inRBM20.Methods:Trio whole-exome sequencing(WES)was performed.Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics(ACMG).Results:We identified two distinctde novo variants inRBM20(one per patient)in these two patients with LVNC.Both variants have been reported in patients with DCM,without the LVNC phenotype.Patient 1 was an 11-year-old girl who had DCM,LVNC,and heart failure;the ratio of noncompacted-to-compacted myocardium was 2.7:1.Ade novo heterozygous variant c.1907G>A(p.Arg636His)in exon 9 was identified in this patient.Patient 2 was a 13-year-old boy who had clinical phenotypes identical to those of Patient 1;the ratio of noncompacted-to-compacted myocardium was 3.2:1 in this patient.WES revealed ade novo heterozygous variant c.1909A>G(p.Ser637Gly)in exon 9.Both variants were previously characterized as pathogenic,and our study classified them as pathogenic variants based on the ACMG guidelines.Interpretation:We found that two patients with LVNC had variants inRBM20.Our results extended the clinical spectrum of the twoRBM20 variants and illustrated that the same variant inRBM20 can cause DCM,with or without the LVNC phenotype.
基金National Natural Science Foundation of China (NSFC31525022, 91440109, and 31472045)+2 种基金Chinese Academy of Sciences (KJZD-EW-L12) to Y.-Z.X.NSFC (31570821) to Y.-J.F.NSFC (31522053, 91631103) to S. Z.
文摘Serine/arginine (SR)-rich proteins are critical for the regulation of alternative splicing (AS), which generates multiple mRNA isoforms from one gene and provides protein diversity for cell differentiation and tissue development. Genetic evidence suggests that Drosophila genital-specific overexpression of SR-related nuclear matrix protein of 160 kDa (SRml60), an SR prot&n with a PWI RNA-binding motif, causes defective development only in male flies and results in abnonnal male genital structures and abnormal testis. However, the molecular characterization of SRm160 is limited. Using the high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) method in two sex-specific embryonic cell lines, S2 from the male and Kc from the female, we first identified the genome-wide RNA-binding characteristics of SRm160, which preferred binding to the exonic tri-nucleotide repeats GCA and AAC. We then validated this binding through both in vitro gel-shift assay and in vivo splicing of minigenes and found that SRm160 level affects AS of many transcripts. Furthermore, we identified 492 differential binding sites (DBS) of SRm160 varying between the two sex-specific cell lines.Among these DBS-containing genes, splicing factors were highly enriched, including transformer, a key regulator in the sex determination cascade. Analyses of fly mutants demonstrated that the SRm160 level affects AS isoforms of transformer. These findings shed crucial light on SRm160's RNA-binding specificity and regulation of AS in Drosophila sex determination and development.
