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Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.

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Τίτλος: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
Συγγραφείς: Murphy MR; Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. mrm2267@cumc.columbia.edu.; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA. mrm2267@cumc.columbia.edu., Ganapathi M; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Rotlevi ER; Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA., Lee TM; Department of Pediatrics, Columbia University Medical Center Irving Medical Center, New York, NY, USA., Fisher JM; Department of Pediatrics, Columbia University Medical Center Irving Medical Center, New York, NY, USA., Patel MV; Department of Pediatrics, Nicklaus Children's Hospital, Miami, FL, USA.; Children's Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA., Jayakar P; Division of Genetics and Metabolism, Nicklaus Children's Hospital, Miami, FL, USA., Buchanan A; Illumina Inc, San Diego, CA, USA., Rippert AL; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Ahrens-Nicklas RC; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Nair D; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Nayak SS; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India., Anand A; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India., Shukla A; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India., Soni RK; Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA., Yin Y; Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.; Barnard College, Columbia University, New York, NY, USA., Yang F; Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA., Garcia EJ; Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Reilly MP; Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Chung WK; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Wu X; Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. xuebing.wu@columbia.edu.; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA. xuebing.wu@columbia.edu.
Πηγή: Nature cardiovascular research [Nat Cardiovasc Res] 2026 Jan; Vol. 5 (1), pp. 51-66. Date of Electronic Publication: 2026 Jan 06.
Τύπος έκδοσης: Journal Article; Case Reports
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer Nature Country of Publication: England NLM ID: 9918284280206676 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2731-0590 (Electronic) Linking ISSN: 27310590 NLM ISO Abbreviation: Nat Cardiovasc Res Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Springer Nature, [2022]-
Ιατρικοί όροι (MeSH): Cardiomyopathy, Dilated*/genetics , Cardiomyopathy, Dilated*/metabolism , Cardiomyopathy, Dilated*/pathology , Myocytes, Cardiac*/metabolism , Myocytes, Cardiac*/pathology , Ribosomal Proteins*/genetics , Ribosomal Proteins*/metabolism , Ribosomes*/metabolism , Ribosomes*/pathology , Ribosomes*/genetics , Mutation, Missense*, RNA, Ribosomal/metabolism ; RNA, Ribosomal/genetics ; Adult ; Animals ; Female ; Humans ; Male ; Genetic Predisposition to Disease ; Pedigree ; Phenotype ; Ribosomal Protein L3 ; Infant ; Child ; Middle Aged
Περίληψη: The heart uses a muscle-specific ribosome in cardiomyocytes, where the ribosomal protein RPL3 is replaced by its paralog RPL3L. Rare biallelic RPL3L mutations cause fatal neonatal dilated cardiomyopathy, yet the mechanisms that link genotype to heart failure are unclear. Despite the recessive inheritance pattern in humans, Rpl3l knockout mice show no overt cardiac phenotype, probably because of compensatory RPL3 upregulation through unknown mechanisms. Here we report four additional cases and propose a unifying pathogenetic model by integrating human genetics, patient tissues and isogenic cell models. Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private allele. Whereas non-hotspot variants phenocopy knockout and allow RPL3 compensation, hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation by preserving the role of RPL3L in repressing RPL3 via unproductive splicing. These findings establish combined loss-of-function and gain-of-function mechanisms for RPL3L-associated cardiomyopathy and inform genetic screening, diagnosis and therapeutic development.
(© 2026. The Author(s).)
Competing Interests: Competing interests: X.W. is a member of the scientific advisory board for Epitor Therapeutics. W.K.C. serves on the board of directors at Prime Medicine. The other authors declare no competing interests.
Σχόλια: Update of: bioRxiv. 2025 Jan 28:2025.01.02.630345. doi: 10.1101/2025.01.02.630345.. (PMID: 39803500)
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Grant Information: P30 CA013696 United States CA NCI NIH HHS; R01 HL171664 United States HL NHLBI NIH HHS; United Kingdom WT_ Wellcome Trust; UL1 TR001873 United States TR NCATS NIH HHS; S10 OD030282 United States OD NIH HHS; S10 OD020056 United States OD NIH HHS
Substance Nomenclature: 0 (Ribosomal Protein L3)
0 (Ribosomal Proteins)
0 (RNA, Ribosomal)
0 (RPL3 protein, human)
Entry Date(s): Date Created: 20260106 Date Completed: 20260116 Latest Revision: 20260422
Update Code: 20260422
PubMed Central ID: PMC12811116
DOI: 10.1038/s44161-025-00761-8
PMID: 41495453
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2731-0590
DOI:10.1038/s44161-025-00761-8