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http://hdl.handle.net/2445/201877
Title: | RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia |
Author: | Launay, Nathalie Ruiz, Montserrat Planas Serra, Laura Verdura, Edgard Rodríguez Palmero, Agustí Schlüter, Agatha Goicoechea, Leire Guilera, Cristina Casas, Josefina Campelo, Felix Jouanguy, Emmanuelle Casanova, Jean Laurent Boespflug‐Tanguy, Odile Vazquez Cancela, Maria González Gutiérrez-Solana, Luis Casasnovas, Carlos Area Gomez, Estela Pujol, Aurora |
Keywords: | Paraplegia Metabolisme dels lípids Neurosciences Paraplegia Lipid metabolism Neurociències |
Issue Date: | 17-Jul-2023 |
Publisher: | American Society for Clinical Investigation |
Abstract: | The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid-droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development. |
Note: | Reproducció del document publicat a: https://doi.org/10.1172/JCI162836 |
It is part of: | Journal of Clinical Investigation, 2023, vol. 133, num. 14, p. e162836 |
URI: | http://hdl.handle.net/2445/201877 |
Related resource: | https://doi.org/10.1172/JCI162836 |
ISSN: | 1558-8238 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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