Ribonucleases as Crucial Factors in Mendelian Disorders: A Review

A recent review published in the journal *Genes & Diseases* has highlighted the significant role of ribonucleases (RNases) in the molecular mechanisms underlying Mendelian disorders. The study, authored by Dr. Aditi Dutta and colleagues from the University of California, Los Angeles (UCLA), emphasizes how these essential enzymes, which are pivotal in maintaining RNA metabolism, are implicated in a variety of human diseases when genetic mutations disrupt their function.

Ribonucleases are enzymes that degrade RNA molecules, and their proper functioning is critical for various cellular processes. According to Dr. Dutta, "When RNases are mutated, they lose their ability to regulate RNA dynamics effectively, leading to a series of pathological conditions including neurological, growth-related, hematopoietic, and mitochondrial dysfunctions" (Dutta et al., 2025).

The review identifies several severe disease phenotypes linked to loss-of-function mutations in RNases, including Aicardi-Goutières syndrome, amyotrophic lateral sclerosis (ALS), Perlman syndrome, and progressive external ophthalmoplegia. These disorders are characterized by mutations that either directly affect the catalytic core of RNases or alter their RNA recognition and localization motifs, resulting in significant clinical implications.

The importance of RNases extends beyond mere enzymatic activity; many of these enzymes are highly conserved across species, underscoring their fundamental biological roles. This conservation allows for comparative studies using model organisms such as mice and zebrafish, which have been instrumental in elucidating the genetic pathways involved in these disorders. Dr. Thomas Lee, a geneticist at Stanford University, states that "the use of model organisms not only helps in understanding the disease mechanisms but also accelerates the identification of potential therapeutic strategies through functional dissection of mutations" (Lee, 2025).

The review further discusses how mutations in RNases can disrupt the biogenesis and turnover of small non-coding RNAs, microRNAs, and other RNA classes, which are essential for cellular homeostasis. In neurological diseases, for instance, compromised RNase function can lead to disrupted neuronal translation, impaired immune surveillance, and hindered RNA clearance mechanisms. This disruption is believed to contribute to neuroinflammation and synaptic dysfunction, critical pathways in the pathophysiology of neurodegenerative diseases.

In growth disorders, mutations in RNases have been shown to derail the PI3K/AKT/mTOR signaling pathway, promoting unchecked cell proliferation and organ overgrowth. Dr. Emily Chen, a biochemist at Johns Hopkins University, elaborates on this, noting that "the relationship between RNase mutations and upregulated growth signals indicates a complex interplay that drives pathologies requiring integrated therapeutic approaches" (Chen, 2025).

Moreover, the review highlights the implications of RNase mutations on hematopoiesis. Defects in telomere maintenance and ribosome maturation due to RNase dysfunction can significantly impact hematopoietic stem cell renewal, thereby compromising blood cell production. This aspect of RNase activity is particularly pivotal given the rising incidence of blood-related disorders.

The study concludes by emphasizing the need for further research into RNase activity and its role in Mendelian disorders to bridge the gap between genetic mutations and their phenotypic expressions. Continued advancements in single-cell transcriptomic technologies and cross-species genetic tools are expected to facilitate the discovery of candidate disease genes and the development of novel therapeutic strategies.

Overall, this review serves as a call to action for researchers in the field, highlighting the indispensable role of ribonucleases in Mendelian genetics and their potential as targets for future therapeutic interventions. As Dr. Dutta succinctly puts it, "Understanding the molecular underpinnings of RNase-related disorders may unlock new avenues for treatment and improve the lives of those affected by these debilitating conditions" (Dutta et al., 2025).