Knockout mouse models as a resource for rare diseases studies

Abstract Rare diseases (RDs) are a challenge for medicine due to their heterogeneous clinical manifestation and low prevalence. There is a lack of specific treatments and only a few hundred of the approximately 7.000 RDs have an approved regime. Rapid technological development in genome sequencing enables the mass identification of potential candidates that in their mutated form could trigger diseases but are often not confirmed to be causal. Knockout (KO) mouse models are essential to understand the causality of genes by allowing highly standardized research into the pathogenesis of diseases. The German Mouse Clinic (GMC) is one of the pioneers in mouse research and successfully uses (preclinical) data obtained from single-gene KO mutants for research into monogenic RDs. As part of the International Mouse Phenotyping Consortium and INFRAFRONTIER, the pan-European consortium for modelling human diseases, the GMC expands these preclinical data towards global collaborative approaches with researchers, clinicians and patient groups. Here, we highlight proprietary genes like proof-of-concept RD targets ( Nacc1, Bach2, Klotho alpha ). We focus on recognized RD genes with no pre-existing KO mouse models ( Kansl1l, Acsf3, Pcdhgb2, Rabgap1, Cox7a2 ) and novel phenotypes capable of optimising clinical diagnostic ( Rabgap1, Pcdhgb2 ). In addition, we present yet unknown RD genes with intriguing phenotypic data ( Zdhhc5, Wsb2 ) not presently associated with known human RDs that may have a justified case to suggest causal genes underlying so far undiagnosed diseases. This report provides comprehensive evidence for genes that when deleted cause differences in the KO mouse across multiple organs, providing a huge translational potential for further understanding monogenic RDs and their clinical spectrum. Genetic KO studies in mice are valuable to explore further the underlying physiological mechanisms and its overall therapeutic potential.