A new review brings to light the pivotal role of ribonucleases (RNases) in shaping the molecular foundation of Mendelian disorders . These essential enzymes, known for maintaining RNA metabolism , are revealed as central players in a diverse spectrum of human diseases. When disrupted by genetic mutations, RNases lose their ability to regulate RNA dynamics, giving rise to neurological , growth-related , hematopoietic , and mitochondrial dysfunctions .
At the heart of these disorders are loss-of-function mutations that compromise RNase activity either directly at the catalytic core or through alterations in their RNA recognition and localization motifs . These defects are often associated with severe disease phenotypes, including Aicardi-Goutières syndrome , amyotrophic lateral sclerosis , Perlman syndrome , and progressive external ophthalmoplegia , among others. Many of the RNases involved in these disorders are highly conserved across species , underscoring their fundamental biological importance.
The review explores how small non-coding RNAs , miRNAs , piRNAs , and other RNA classes depend on RNase regulation for their biogenesis and turnover. In neurological diseases, the loss of RNase function disrupts asymmetric neuronal translation , interferes with immune surveillance , and hinders RNA clearance mechanisms , leading to neuroinflammation and synaptic dysfunction . In growth disorders, mutations derail the PI3K/AKT/mTOR signaling axis , promoting unregulated cell proliferation and organ overgrowth . In the blood, RNase mutations impair telomere maintenance and ribosome maturation , compromising hematopoietic stem cell renewal .
To bridge the gap between mutation and disease, the article highlights the indispensable value of model organisms . Comparative studies across mice , zebrafish , flies , worms , and yeast reveal conserved genetic pathways and provide critical insight into disease pathogenesis . These models allow the functional dissection of mutations, mapping their consequences on RNA stability , protein synthesis , and cellular stress responses . The availability of single-cell transcriptomic atlases and cross-species genetic tools accelerates the identification of candidate disease genes and the testing of therapeutic strategies .
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Reference
Annasha Dutta, Anastasiia Zaremba, Paulina Jackowiak, Ribonucleases in Mendelian disease: Characterization and insight from model organisms, Genes & Diseases, Volume 12, Issue 5, 2025, 101613, https://doi.org/10.1016/j.gendis.2025.101613
Funding Information :
National Science Centre, Poland 2019/35/B/NZ2/02658
Genes & Diseases