Knockout mouse models as a resource for the study of rare diseases

Abstract

Rare diseases (RDs) are a challenge for medicine due to their heterogeneous clinical manifestations 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 (IMPC) and INFRAFRONTIER, the pan-European consortium for modeling human diseases, the GMC expands these preclinical data toward global collaborative approaches with researchers, clinicians, and patient groups.Here, we highlight proprietary genes that when deleted mimic clinical phenotypes associated with known RD targets (Nacc1, Bach2, Klotho alpha). We focus on recognized RD genes with no pre-existing KO mouse models (Kansl1l, Acsf3, Pcdhgb2, Rabgap1, Cox7a2) which highlight novel phenotypes capable of optimizing clinical diagnosis. In addition, we present genes with intriguing phenotypic data (Zdhhc5, Wsb2) that are not presently associated with known human RDs.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 further explore the underlying physiological mechanisms and their overall therapeutic potential.

Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors

“…Thus, we did not extensively characterize the potential morphological and behavioral abnormalities in Wsb2 -/- mice. However, recent large-scale mouse phenotype analyses conducted by the International Mouse Phenotyping Consortium (IMPC) have reported abnormalities in tooth morphology, locomotor activity, retina, heart, osmotic and electrolyte balance, as well as male infertility in Wsb2 -/- mice 39 . It remains unclear whether these abnormalities are a result of NOXA accumulation and subsequent dysregulated apoptosis.…”

Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families

“… 44 In particular, knockout mouse models have been an invaluable resource for the study of rare diseases. 45 , 46 However, despite being such a well-established model, the suitability and validity of the mouse for recapitulating human disease have been controversial, for example, in studies comparing human and mouse immune functions and responses. 47-50 Notably, according to a report, null mutations in human and mouse orthologs often result in different phenotypes, and more than 20% of human essential genes have nonessential orthologs in mice.…”

Mouse phenome database: curated data repository with interactive multi-population and multi-trait analyses

“…A major new addition is the first integration of data from the International Mouse Phenotyping Consortium (IMPC) (Peterson and Murray 2022 ; Groza et al 2023 ) which includes the NIH Knock-out Mouse Phenotyping (KOMP) centers. Several recent studies have reported using KOMP knockout mice (Basilico et al 2022 ; Brommage and Ohlsson 2019 ; Cacheiro et al 2019 ; da Silva-Buttkus et al 2023 ; Higgins et al 2022 , and many others). The IMPC consortium has characterized thousands of single-gene deletion mutations on a wide array of phenotyping assays coordinated across centers.…”