Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.

ABSTRACT: 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,

SUBMITTER: Murphy MR 

PROVIDER: S-EPMC12811116 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature