Human patients carrying genetic mutations in RNA binding motif 20 (RBM20) develop a clinically aggressive dilated cardiomyopathy (DCM). Genetic mutation knockin (KI) animal models imply that altered function of the arginine-serine-rich (RS) domain is crucial for severe DCM. To test this hypothesis, we generated an RS domain deletion mouse model (
Rbm20
ΔRS
). We showed that
Rbm20
ΔRS
mice manifested DCM with mis-splicing of RBM20 target transcripts. We found that RBM20 was mis-localized to the sarcoplasm in
Rbm20
ΔRS
mouse hearts and formed RBM20 granules similar to those detected in mutation KI animals. In contrast, mice lacking the RNA recognition motif showed similar mis-splicing of major RBM20 target genes but did not develop DCM or exhibit RBM20 granule formation. Using in vitro studies with immunocytochemical staining, we demonstrated that only DCM-associated mutations in the RS domain facilitated RBM20 nucleocytoplasmic transport and promoted granule assembly. Further, we defined the core nuclear localization signal (NLS) within the RS domain of RBM20. Mutation analysis of phosphorylation sites in the RS domain suggested that this modification may be dispensable for RBM20 nucleocytoplasmic transport. Collectively, our findings revealed that disruption of RS domain–mediated nuclear localization is crucial for severe DCM caused by NLS mutations.
Human patients carrying genetic mutations in RNA binding motif 20 (RBM20) develop a clinically aggressive dilated cardiomyopathy (DCM). RBM20 is a splicing factor with two canonical domains, an RNA recognition motif (RRM) and an arginine-serine rich (RS) domain. RRM loss-of-function disrupts the splicing of RBM20 target transcripts and leads to systolic dysfunction without overt DCM, while mutations in the RS domain precipitate DCM. We show that mice lacking the RS domain (Rbm20deltaRS) manifest DCM with mis-splicing of RBM20 target transcripts. We found that RBM20 is mis-localized in Rbm20ΔRS mice but not in mice lacking the RRM, which are also deficient in RBM20 splicing. We determine that the RS domain, not other domains including the RRM, is critical for RBM20 nuclear import and define the core nuclear localization signal (NLS) within this domain. Mutation analysis of phosphorylation sites within the RS domain indicate that phosphorylation is dispensable for RBM20 nuclear import. Collectively, our findings establish disruption of the NLS in RBM20 as a causative mechanism in DCM through nucleocytoplasmic transport.
The regional water cycle is increasingly reflecting the dual role of natural and social processes, and is affected by global climate change and strong human intervention. The study of water cycle health evaluation has provided guidance to urban planning, development, and resource management. In this study, a water cycle health evaluation method based on EFAST-Cloud model is proposed, and Henan Province of China is selected as a typical study area. The water cycle health status is evaluated from four dimensions of water ecology, water quality, water abundance, and water utilization. The evaluation results are compared with those of fuzzy comprehensive evaluation as well. It is shown that the established EFAST-Cloud model results of assessment are consistent with the Fuzzy comprehensive evaluation method, while it has the advantage of being able to evaluate the proportion of each grade in detail by reflecting the randomness and fuzziness of the evaluation. According to the statistical data from 2007 to 2018, the whole area is in a sub-healthy state. During the 12-year period, the health status of the water cycle has been improved year by year. The research results can provide theoretical basis for repairing regional water environment and promoting regional sustainability
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.