ABSTRACT: Genetic variation underlies much of human diversity, including differences in disease severity, progression, and response to therapy. Yet, most mouse models used to study genetic diseases and evaluate therapeutic interventions are maintained on a single genetic background, limiting their ability to reflect the genetic heterogeneity observed in patients. This limitation extends even to Mendelian disorders such as LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD), where individuals with the same pathogenic mutation in LAMA2 gene often exhibit variable clinical presentations. Current preclinical mouse models of LAMA2-CMD, constrained by their genetic uniformity, fail to capture this variability. Goal: In this study, we aimed to develop genetically diverse mouse models that better recapitulate the spectrum of disease phenotypes seen in LAMA2-CMD. We leveraged the BXD recombinant inbred panels, which are unique families of advanced intercrosses between C57BL/6J and DBA/2J mice with well-documented SNP profiles and phenotypes, to assess the impact of genetic background on disease expressivity. Methods: We generated LAMA2-CMD mouse models carrying the same Lama2. c.271+1 G>A mutation on C57BL/6J, DBA/2J, BXD67, and BXD87 backgrounds, referred to as CMD-B6, CMD-D2, CMD-67, and CMD-87 mice, respectively. We performed longitudinal assessments of body weight, forelimb grip strength, locomotor activity, and analyzed tibialis anterior (TA) muscle contractile force, muscle histology and transcriptomic profiles across all genotypes. Results: All CMD mice exhibited failure to thrive and reduced forelimb grip strength at 8 and 25 weeks. In contrast, reductions in locomotor activity and TA muscle force were observed only in select strains. Histological analyses revealed smaller muscle fiber diameter in CMD-B6 and CMD-87 compared to their WT littermates, while CMD-67 showed no difference relative to controls. Transcriptomic profiling revealed consistent upregulation of immune-related genes and leukocyte-associated pathways across all CMD strains. Notably, CMD-67 mice uniquely exhibited concurrent enrichment of both immune- and muscle developmental pathways. In contrast, downregulated pathways were largely strain-specific and included changes in developmental and metabolic processes. Conclusion: These findings demonstrate that while body weight and forelimb weakness are consistent across genetic backgrounds, other traits such as mobility, muscle force, and muscle growth, are strongly influenced by genetic backgrounds. Moreover, strain-dependent transcriptomic signatures highlight how genetic background can influence the molecular interpretation of disease. Overall, this work establishes a novel LAMA2-CMD mouse panel as a valuable resource for future studies, including identification of disease modifiers and evaluation of therapeutic responses, and provides evidence that preclinical models incorporating genetic diversity may better translate to human disease.
