Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium

Abstract

Although next generation sequencing has revolutionised the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by our lack of knowledge of function and pathobiological mechanism for most genes. To address this challenge, the International Mouse Phenotyping Consortium (IMPC) is creating a genome- and phenome-wide catalogue of gene function by characterizing new knockout mouse strains across diverse biological systems through a broad set of standardised phenotyping tests, with all mice made readily available to the biomedical community. Analysing the first 3328 genes reveals models for 360 diseases including the first for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations are novel, providing the first functional evidence for 1092 genes and candidates in unsolved diseases such as Arrhythmogenic Right Ventricular Dysplasia 3. Finally, we describe our role in variant functional validation with the 100,000 Genomes and other projects.

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

“…This suggests that I1 and I2 have distinct functions in other tissues. Fifth, global KOs of CPI-17 or its homolog GBP1, were associated with decreased blood pressure and abnormal heart morphology, respectively (Table 2) [48,70]. Decreased blood pressure was also observed in mice expressing only a non-phosphorylatable CPI-17 mutant (CPI-17 T38A ) that acts as a constitutively inactive PP1 inhibitor, confirming the importance of PP1:CPI-17 interaction for this phenotype.…”

“…In contrast to total PP1α and PP1γ KO mice, the global deletion of PP1β led to pre-weaning mortality (i.e. homozygotes died before an age of 3-4 weeks) as described by the International Mouse Phenotyping Consortium 1 (Table 1) [48]. This lethal phenotype suggests essential PP1β-specific functions that cannot be compensated for by the remaining PP1 isoforms, likely because of the existence of PP1β selective PIPs.…”

“…The selective deletion of individual PP1 isoforms in hearts 1 International Mouse Phenotyping Consortium produces KO mice and phenotypes them according to fully validated and standardized protocols [48].…”

Optimizing PCR for Mouse Genotyping: Recommendations for Reliable, Rapid, Cost Effective, Robust and Adaptable to High‐Throughput Genotyping Protocol for Any Type of Mutation

“…Instead, it is recommended that the PCR assay specifically identify each line and each possible allele derived from the stock mutant line. For example, the International Knockout Mouse Consortium is creating a catalog of mammalian gene function (Meehan et al, 2017) and reports the generation of over 5000 new mouse mutant strains all harboring a lacZ reporter cassette and providing conditional inactivation potential. An optimized protocol allows researchers to evaluate all possible genotypes and the integrity of the targeting event ( Fig.…”

“…With this strategy, combining common primers with different, unique primers allows all possible alleles to be detected. Figure 2 provides an example of primer design optimization for genotyping mutant models generated by the International Mouse Phenotyping Consortium (IMPC https://www.mousephenotype.org; Meehan et al, 2017). Primers are positioned in the wild-type sequence on the DNA region that differs between the wild-type allele and the mutant allele(s).…”