Fois Adrien, Deschênes Sonia, Bourel Capucine, Beauchamp Claudine, Lombard-Vadnais Félix, Ruiz Matthieu, Charron Guy, Coderre Lise, Rioux John D, Lesage Sylvie
Axe Immunologie-Oncologie, Centre de Recherche de L'Hôpital Maisonneuve-Rosemont, Montréal, Québec Canada.
Département de Microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Québec Canada.
J Rare Dis (Berlin). 2025;4(1):31. doi: 10.1007/s44162-025-00094-x. Epub 2025 Jul 1.
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 () 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 on immune cell function.
As genetic deletion of is not viable, we generated two conditional mouse models: a model for systemic deletion of and a knock-in (KI) model carrying the most common LSFC pathogenic variant in Quebec, NM_133259.4(LRPPRC):c.1061C > T (p.Ala354Val).
We demonstrate that is an essential gene even in adult mice, as systemic deletion of leads to prominent weight loss and mortality. We also find an increase in lactate levels, a symptom of metabolic crises in LSFC. deletion and pathogenic variant affect various immune cell subsets, with a strong impact on B cell development and proliferation.
We generated a viable disease-relevant mouse model to study the role of in vivo and find that disruption of strongly impairs B cell development and proliferation.
The online version contains supplementary material available at 10.1007/s44162-025-00094-x.
法裔加拿大利氏综合征（LSFC）是一种罕见的常染色体隐性代谢紊乱疾病，其特征为严重的乳酸酸中毒危机和早期死亡。LSFC患者在富含亮氨酸的五肽重复序列（LRPPRC）核基因中携带变异，这会导致呼吸链复合物缺陷和线粒体功能障碍。线粒体呼吸调节细胞代谢活动，而细胞代谢活动会影响许多细胞过程，包括免疫细胞的分化和功能。本研究的目的是确定LRPPRC对免疫细胞功能的作用。
由于LRPPRC的基因缺失无法存活，我们构建了两种条件性小鼠模型：一种用于全身性缺失LRPPRC的模型，以及一种携带魁北克最常见的LSFC致病变异NM_133259.4(LRPPRC):c.1061C>T（p.Ala354Val）的敲入（KI）模型。
我们证明即使在成年小鼠中LRPPRC也是一个必需基因，因为全身性缺失LRPPRC会导致明显的体重减轻和死亡。我们还发现乳酸水平升高，这是LSFC代谢危机的一种症状。LRPPRC缺失和致病变异会影响各种免疫细胞亚群，对B细胞发育和增殖有强烈影响。
我们构建了一个可行的与疾病相关的小鼠模型来研究LRPPRC在体内的作用，并发现LRPPRC的破坏会严重损害B细胞发育和增殖。
在线版本包含可在10.1007/s44162-025-00094-x获取的补充材料。
