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

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 () 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.

METHODS

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).

RESULTS

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.

CONCLUSIONS

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.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s44162-025-00094-x.