Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy
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.
Authors
- Amanda Buchanan
- Aakanksha Anand (ORCID: https://orcid.org/0000-0002-3458-0176)
- Muredach P. Reilly (ORCID: https://orcid.org/0000-0002-3035-9386)
- Michael R. Murphy (ORCID: https://orcid.org/0000-0002-0470-5791)
- Esther Rotlevi (ORCID: https://orcid.org/0000-0001-8996-3169)
- Gaurav Soni (ORCID: https://orcid.org/0000-0003-1614-0748)
- Shalini S. Nayak (ORCID: https://orcid.org/0000-0001-9521-7031)
- Xuebing Wu
- A. Rippert
- Yue Yin
- Megha Patel
- Divya R Nair
- Feiyue Yang
- Parul Jayakar (ORCID: https://orcid.org/0000-0003-4290-5118)
- Mythily Ganapathi
- Joshua M. Fisher
- Anju Shukla
- Wendy K. Chung
- Teresa M. Lee
- Enrique J. Garcia
- Rebecca C. Ahrens-Nicklas
Institutions
- Children's Hospital of Wisconsin (US)
- Boston Children's Hospital (US)
- Children's Hospital of Philadelphia (US)
- Harvard University (US)
- Manipal Academy of Higher Education (IN)
- Illumina (United States) (US)
- Medical College of Wisconsin (US)
- Columbia University Irving Medical Center (US)
- Miami Children's Hospital (US)
- Kasturba Medical College, Manipal (IN)
- Columbia University (US)
- University of Pennsylvania (US)
- Barnard College (US)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2026-01-06
- DOI
- https://doi.org/10.1038/s44161-025-00761-8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Heart Association
- Wellcome Trust
- Department of Biotechnology, Ministry of Science and Technology, India
- The Wellcome Trust DBT India Alliance
- National Institutes of Health
- Irving Medical Center, Columbia University
- National Heart, Lung, and Blood Institute
- National Cancer Institute