Generating a Preclinical Model for PITPNM3 and Evaluating Genotype-Phenotype Concordance: Insights from a Mouse Model

PITPNM3 has been identified as a crucial gene associated with various phenotypes of retinal disease in humans; however, detailed mechanisms through which PITPNM3 mutations result in these conditions are not fully understood. In this study, we aimed to generate such a preclinical mouse model and evaluate its relevance to human PITPNM3-related conditions. Heterozygous mice were bred to obtain a homozygous genotype, aiming to mimic the human genetic condition. Subsequent phenotyping and genetic segregation analyses were conducted along with electrophysiological studies and histological examinations. Full-field electroretinogram analysis revealed a reduced cone response although the severity was not as pronounced as observed in humans with PITPNM3-related conditions. Histologically, the retinal structure appeared largely unchanged, indicating a discordance between functional impairment and morphological changes. In our preclinical mouse model, the observed phenotypic changes were not as severe as those found in humans with PITPNM3-related conditions and this discrepancy points to a potentially different disease progression trajectory in the mouse model. These findings highlight the importance of longer follow-up periods in such studies and the need for further research to elucidate the genotype-phenotype relationship in PITPNM3.