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Purpose <p>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 (<i>LRPPRC</i>) 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 <i>Lrpprc</i> on immune cell function.</p> Methods <p>As genetic deletion of <i>Lrpprc</i> is not viable, we generated two conditional mouse models: a model for systemic deletion of <i>Lrpprc</i> and a knock-in (KI) model carrying the most common LSFC pathogenic variant in Quebec, NM_133259.4(LRPPRC):c.1061C &gt; T (p.Ala354Val).</p> Results <p>We demonstrate that <i>Lrpprc</i> is an essential gene even in adult mice, as systemic deletion of <i>Lrpprc</i> leads to prominent weight loss and mortality. We also find an increase in lactate levels, a symptom of metabolic crises in LSFC. <i>Lrpprc</i> deletion and pathogenic variant affect various immune cell subsets, with a strong impact on B cell development and proliferation.</p> Conclusions <p>We generated a viable disease-relevant mouse model to study the role of <i>Lrpprc</i> in vivo and find that disruption of <i>Lrpprc</i> strongly impairs B cell development and proliferation.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Adrien Fois,
  • Sonia Deschênes,
  • Capucine Bourel,
  • Claudine Beauchamp,
  • Félix Lombard-Vadnais,
  • Matthieu Ruiz,
  • Guy Charron,
  • Lise Coderre,
  • Christine Des Rosiers,
  • Azadeh Alikashani,
  • Bruce G. Allen,
  • Chantale Aubut,
  • Chantal Bémeur,
  • Yan Burelle,
  • François Labarthe,
  • Jeannine Landry,
  • Catherine Laprise,
  • Geneviève Lavallée,
  • Pierre Lavoie,
  • Bruno Maranda,
  • Charles Morin,
  • Yvette Mukaneza,
  • Tamiko Nishimura,
  • Marie-Ève Rivard,
  • Florin Sasarman,
  • Eric A. Shoubridge,
  • Jessica Tardif,
  • Julie Thompson Legault,
  • Nancy Tremblay,
  • Vanessa Tremblay-Vaillancourt,
  • Luc Vachon,
  • Josée Villeneuve,
  • John D. Rioux,
  • Sylvie Lesage

摘要

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.