Disruption of Lrpprc affects B cell development and proliferation in a mouse model of Leigh Syndrome French Canadian type

Disruption of Lrpprc affects B cell development and proliferation in a mouse model of Leigh Syndrome French Canadian type

Abstract Purpose Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry variants in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) nuclear gene, which lead to defect...

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Main Authors: Adrien Fois, Sonia Deschênes, Capucine Bourel, Claudine Beauchamp, Félix Lombard-Vadnais, Matthieu Ruiz, Guy Charron, Lise Coderre, LSFC Consortium, John D. Rioux, Sylvie Lesage
Format: Article
Language:English
Published: Springer 2025-07-01
Series:Journal of Rare Diseases
Subjects:
LSFC
LRPPRC
Immune cells
Mitochondria
Proliferation
B cells
Online Access:https://doi.org/10.1007/s44162-025-00094-x
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Summary:Abstract Purpose Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry variants in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) nuclear gene, which lead to defects in the respiratory chain complexes and mitochondrial dysfunction. Mitochondrial respiration modulates cellular metabolic activity, which impacts many cell processes, including the differentiation and function of immune cells. The purpose of this study is to define the role of Lrpprc on immune cell function. Methods As genetic deletion of Lrpprc is not viable, we generated two conditional mouse models: a model for systemic deletion of Lrpprc and a knock-in (KI) model carrying the most common LSFC pathogenic variant in Quebec, NM_133259.4(LRPPRC):c.1061C > T (p.Ala354Val). Results We demonstrate that Lrpprc is an essential gene even in adult mice, as systemic deletion of Lrpprc leads to prominent weight loss and mortality. We also find an increase in lactate levels, a symptom of metabolic crises in LSFC. Lrpprc deletion and pathogenic variant affect various immune cell subsets, with a strong impact on B cell development and proliferation. Conclusions We generated a viable disease-relevant mouse model to study the role of Lrpprc in vivo and find that disruption of Lrpprc strongly impairs B cell development and proliferation.
ISSN:2731-085X

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