Many thanks also to our collaborators, in particular Mythily Ganapathi who introduced us to some of the early cases.

These findings challenge the common view that autosomal recessive diseases result solely from loss-of-function mutations. Instead, we propose a model where gain-of-toxicity contributes to disease pathogenesis. We welcome feedback and discussion.

Using isogenic human cardiomyocyte-like cells, we confirm that hotspot RPL3L mutations cause ribosome depletion and severe growth defects, distinct from simple RPL3L loss-of-function.

Unlike in KO mice, where RPL3 compensates for the absence of RPL3L, we observe no RPL3 upregulation in patient hearts, likely worsening ribosome loss and cellular dysfunction.

Hotspot RPL3L mutations mislocalize to the nucleus, disrupt ribosome biogenesis by sequestering 28S rRNA, and interfere with essential ribosome assembly factors. This leads to a shortage of functional 60S ribosomal subunits.

Our key finding: RPL3L-linked DCM is driven by toxic hotspot mutations, rather than simple loss-of-function (LoF). Patients typically inherit: ✅ One hotspot toxic mutation (D308N, G27D) ✅ One LoF mutation (truncation, splice-site, or low-pathogenicity missense)

In contrast to expectations, RPL3L knockout (KO) mice show only mild cardiac defects. This suggests that disease-causing RPL3L mutations do more than simply disrupt ribosome function.

The heart relies on a muscle-specific ribosome, replacing the core ribosomal protein RPL3 with its paralog, RPL3L. While its function remains poorly understood, mutations in RPL3L lead to a severe, neonatal-onset form of DCM.

Excited to share our new preprint from the @wu_xuebing lab: https://t.co/qvJ1gdN7N3 In it, we identify a gain-of-toxicity mechanism in RPL3L-linked neonatal dilated cardiomyopathy (DCM), challenging the idea that recessive diseases are primarily caused by loss-of-function.

U.K. approves world’s first CRISPR-based medicine, giving greenlight to therapy for sickle cell, thalassemia https://t.co/4g3XA2Bxs4 via @statnews

Base and prime editors induce double-strand breaks, deletions and translocations in hematopoietic cells

The #gnomAD team is proud to announce the release of gnomAD v4! The v4 dataset includes 730,947 exomes & 76,215 genomes, which is ~5x larger than the v2 & v3 releases combined, & includes nearly 120K indivs of non-European genetic ancestry https://t.co/YKXIFlZwSi #ASHG23 (1/11)

Very excited to share our work on cancer nanomedicine now out in @ScienceMagazine. This was a really fun and collaborative project co-led by @natalie_boehnke and supported by an amazing group of scientists @kochinstitute @broadinstitute @DFBC_PedCare

Stressful steps: Progress and challenges in understanding stress-induced mRNA condensation and accumulation in stress granules

Are you thinking about performing 40S ribosome footprinting (TCP-seq) or even selective 40S/80S ribosome footprinting (Sel-TCP-seq)? It can seem daunting and too complex 🧐 For this reason we have now published a comprehensive summary of the method(s): https://t.co/fEC0TeLnRu

SHAME ON @illumina. All my labs 150+ iseq and novaseq runs deleted off @BaseSpace. Why? I exceeded 1 TB and didnt check my lab's gmail. There is apparently nothing they can do now. All my lab's data is gone ... I have some backups ...

"Thirteen dubious ways to detect conserved RNA structure" W Gao, A Yang, E Rivas. https://t.co/CoLodcNfk4 Is it a conserved RNA structure, or not? ...or can we even tell?

I pretty regularly share the super plots paper by @samjlord and @MullinsLab with new core users, lab members, and collaborators. It has one of my favorite figures of all time. https://t.co/bPZ0oYefoF

VASA-seq sequences total RNA in single cells, revealing non-coding expression and splicing patterns

fascinating new paper in Cell shows that many insect genomes harbor HUNDREDS of genes derived from bacteria and acquired at some point through horizontal gene transfer among these, a gene from Listeria essential for male butterfly mating behavior https://t.co/bwUi5ntGQE