Computational and translational pipeline to interpret the pathogenicity of human MDN1 variants associated with a novel neurodevelopmental disorder.

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2025.

The human brain develops through a highly coordinated process that relies on the correct production of proteins. A crucial step in this process is ribosome biogenesis, which ensures that ribosomes—the molecular machines responsible for protein production—are properly assembled. Defects in ribosome biogenesis can disrupt protein synthesis and lead to neurodevelopmental disorders (NDDs), heterogeneous conditions characterized by developmental delay, cognitive disabilities, and neurological problems. Midasin1 (MDN1), also known as Rea1, is an important protein that helps build ribosomes. It plays a key role in the transport to the cytoplasm of the ribosomal 60S subunit, where it can function in protein production. Mutations in genes responsible for ribosome maturation may cause NDDs, but with poorly understood mechanisms. Our research focuses on MDN1 because we have identified a group of patients with mutations in this gene who share similar neurodevelopmental symptoms, suggesting MDN1 plays a role in a previously unrecognized NDD. Based on our preliminary studies in yeast, we believe that these MDN1 mutations impair ribosome maturation, leading to defects in protein production that may underlie the observed developmental issues. To explore this, we will combine computational and laboratory techniques. First, we will analyze the genetic and clinical data of affected individuals to better understand the range of symptoms and identify additional patients. Then, we will use computational tools to predict how these variants might alter MDN1 structure and function. Finally, we will study the effects of these variants in human cells, both in laboratory models and in cells from human patients, to determine whether they disrupt ribosomal maturation and transport. Our study will clarify the role of MDN1 in brain development, improve genetic diagnosis for patients with this novel NDD, and set the stage for future research into potential treatments.