RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia
Nathalie Launay, … , Estela Area-Gomez, Aurora Pujol
Nathalie Launay, … , Estela Area-Gomez, Aurora Pujol
Published July 17, 2023
Citation Information: J Clin Invest. 2023;133(14):e162836. https://doi.org/10.1172/JCI162836.
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Research Article Metabolism Neuroscience

RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia

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 RINT1 loss-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.

Authors

Nathalie Launay, Montserrat Ruiz, Laura Planas-Serra, Edgard Verdura, Agustí Rodríguez-Palmero, Agatha Schlüter, Leire Goicoechea, Cristina Guilera, Josefina Casas, Felix Campelo, Emmanuelle Jouanguy, Jean-Laurent Casanova, Odile Boespflug-Tanguy, Maria Vazquez Cancela, Luis González Gutiérrez-Solana, Carlos Casasnovas, Estela Area-Gomez, Aurora Pujol

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Figure 2

RINT1 mutations alter NRZ complex.

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RINT1 mutations alter NRZ complex. (A) Control (CTL) and patient (P1 an...
(A) Control (CTL) and patient (P1 and P3) fibroblasts were subjected to immunoblot analysis using the anti-RINT1, anti-ZW10, and anti-NBAS antibodies. The total amount of α-tubulin (α-tub) was used as a loading control. Blots run in parallel using identical samples are shown. (B) Quantification of RINT1, ZW10, and NBAS protein levels in patient fibroblasts (P1 and P3) relative to the controls (CTL, n = 6). (C–F) Representative confocal images of control (CTL) and patient (P1 and P3) fibroblasts stained with the anti-Calnexin and anti-RINT1 antibodies (C) or the anti-Calnexin and anti-ZW10 antibodies (E). Scale bars: 10 μm. A zoomed-in view is shown for each image with a scale bar of 2 μm. (D and F) Colocalization between RINT1 (D), ZW10 (F), and Calnexin is expressed as Pearson’s coefficient measured for individual cells. n > 20 cells for each genotype. Patient (P1 and P3) and control (CTL, n = 3) fibroblasts. All data are shown as the mean ± SD. Results were obtained from 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001. All data analysis were performed using 1-way ANOVA followed by Tukey’s test for multiple comparisons.