RPL3L encodes a heart and skeletal muscle-specific ribosomal protein that serves as a paralogue of the ubiquitously expressed RPL3 protein 1. RPL3L is a component of the large 60S ribosomal subunit exclusively in striated muscle cells, where it replaces RPL3 in cardiac and skeletal muscle ribosomes 1. Rather than modulating translation of specific transcripts, RPL3L functions by regulating ribosomal subcellular localization and mitochondrial activity in cardiomyocytes 1. RPL3L expression follows a developmental pattern, with cardiac ventricles expressing RPL3 at birth that is gradually replaced by RPL3L in adulthood 2. Loss of RPL3L is compensated by upregulation of RPL3, maintaining normal ribosomal function 2. However, biallelic mutations in RPL3L cause dilated cardiomyopathy type 2D (CMD2D), a severe autosomal recessive neonatal cardiomyopathy with rapid progression to heart failure and high mortality 34. Disease mechanisms involve both gain-of-function toxic variants that disrupt ribosome biogenesis and loss-of-function variants, with recurrent toxic variants sequestering ribosomal RNA and causing cellular toxicity beyond simple ribosome loss 4. RPL3L variants are also associated with adult-onset atrial fibrillation risk 5.