Knockout mice are an important tool for human monogenic heart disease studies

Abstract

Mouse models are relevant to study the functionality of genes involved in human diseases, however, translation of phenotypes can be challenging. Herein, we investigated genes related to monogenic forms of cardiovascular disease based on the Genomics England PanelApp and aligned them to the International Mouse Phenotyping Consortium data. We found 153 genes associated to cardiomyopathy, cardiac arrhythmias or congenital heart disease in humans, 151 with a one2one mouse orthologs. For 37.7% (57/151) viability and heart data captured by electrocardiography, transthoracic echocardiography, morphology and pathology from embryos and young adult mice was available. In knockout mice, 75.4% (43/57) of these genes showed non-viable phenotypes, whereas records of prenatal, neonatal or infant death in humans were found for 35.1% (20/57). Multisystem phenotypes are common, with 58.8% (20/34) of heterozygous (homozygous lethal) and 78.6% (11/14) of homozygous (viable) mice showing cardiovascular, metabolic/homeostasis, musculoskeletal, hematopoietic, nervous system and/or growth abnormalities mimicking the clinical manifestations observed in patients. This IMPC data is critical beyond cardiac diagnostics given its multisystemic nature that allows detecting abnormalities across physiological systems, providing a valuable resource to understand pleiotropic effects.

Computational identification of disease models through cross-species phenotype comparison

“…Other limitations pertaining to the IMPC phenotyping and statistical analysis pipeline involve the heterogeneous implementation of certain phenotypic assays across phenotyping centres, which restricts the ability to capture human phenotypes. This has been discussed in the specific case of congenital heart disorders ( Cacheiro et al, 2023 ). In addition, the human phenotypes described for a disorder vary in frequency and come from case reports in the literature, whereas an associated phenotype as per the IMPC pipeline is only assessed after strict quality-control procedures and statistical significance for the KO compared to a set of matched wild-type mice ( Haselimashhadi et al, 2020 ).…”

“…For each knockout (KO) line, abnormal phenotypes are being ascertained across a range of physiological systems through comparison with wild-type lines ( Kurbatova et al, 2015 ; Haselimashhadi et al, 2020 ). These gene–phenotype associations have been investigated to increase our knowledge on human disease using multiple, complementary approaches: (1) to learn about sexual dimorphism and pleiotropic traits ( Karp et al, 2017 ; Munoz-Fuentes et al, 2022 ), (2) to reveal previously unidentified candidate genes for multiple physiological systems and disease types ( Higgins et al, 2022 ; Bowl et al, 2017 ; Chee et al, 2023 ; Cacheiro et al, 2022 , 2020 ) and (3) to investigate how well the current phenotypic screens capture specific human traits ( Cacheiro et al, 2023 ; Lindovsky et al, 2023 ).…”

From mechanisms of heart failure to clinical heart success

“…To model this process and the consequences of its perturbations, both large and small mammalian models of heart failure are invaluable. In this Special Issue, a paper by Cacheiro et al (2023) reminds us that human genetic cardiomyopathy phenotypes are generally well recapitulated in genetically modified mice, in terms of both cardiac and systemic manifestations of genetic syndromes. As genomics research identifies more and more loci associated with human heart failure, resources such as the International Mouse Phenotyping Consortium can help to identify and model pathogenic mutations.…”