Aurora Pujol Onofre

Institut d'Investigació Biomèdica de Bellvitge

The Rad50-interacting protein 1 (Rint1) is a crucial player in mediating vesicular trafficking between the endoplasmic reticulum (ER) and the Golgi apparatus.

Through comprehensive whole-genome sequencing, we have successfully identified two families characterized by biallelic loss-of-function mutations in the RINT1 gene. Remarkably, these families endured a prolonged period, spanning between 7 to 11 years, awaiting a precise genetic diagnosis.

The affected children exhibited a spectrum of debilitating symptoms, encompassing early onset spastic paraplegia attributable to impaired motor neuron function, ataxia, optic nerve hypoplasia, distinctive dysmorphic features, and liver failure leading to fatality in one case.

Our multifaceted investigations, integrating functional and lipidomic analyses, unveil a profound impact on lipid droplet biogenesis, as well as neutral lipid and phospholipid metabolism. Noteworthy alterations include diminished triglycerides and diglycerides, perturbed phosphatidylcholine/phosphatidylserine ratios, and compromised Lands cycle activity. Additionally, RINT1 mutations induce mitochondrial damage, characterized by elevated intracellular reactive oxygen species (ROS) production, diminished ATP synthesis, membrane depolarization, aberrant cristae ultrastructure, and increased mitochondrial fission.

This study underscores the formidable capability of clinical genomics in unraveling novel ultra-rare diseases, contributing significantly to the expansion of our understanding of cellular metabolism and the intricacies of nervous system development.