Mouse knock-out of exon ENSE00001786716 in the ANK3 gene
* Purpose: Elevated expression of the ANK3 isoform incorporating exon ENSE00001786716 is a risk factor for bipolar disorder and schizophrenia. But very little is known about the function of this isoform other than that there is a strong indication that it is expressed in oligodendrocytes. Generation of a mouse model with a KO of this isoform is essential to determining the localisation and function of this specific isoform.
* Distress for the animals: This specific isoform is only expressed in adult individuals, thus it is highly unlikely to have any effect on development before sexual maturity. Further, we have identified two healthy human samples with homozygous loss-of-function mutations in this exon, thus we expect the phenotype to also be mild in mice.
* Expected scientific benefit: ANK3 is the gene that is most robustly associated with bipolar disorder in genome-wide association studies and has the highest odds ratio. We have demonstrated that this association is highly likely to be driven by this specific isoform. Determining the function of this isoform has the potential to significantly advance our understanding the disorder's etiology.
* Mouse C57BL/6. The mice will be used for organ harvesting and will not be subject to experimentation.
* 3R:
- replacement: the ANK3 protein is a scaffolding adapter protein with many interaction partners, the in vivo context is thus essential to determining its function.
- reduction: we will not sacrifice more animals than strictly necessary for our organ harvesting purposes.
- refinement: the phenotype of this KO is expected to be mild and the animals will not undergo procedures other than routine blood sampling.
* Distress for the animals: This specific isoform is only expressed in adult individuals, thus it is highly unlikely to have any effect on development before sexual maturity. Further, we have identified two healthy human samples with homozygous loss-of-function mutations in this exon, thus we expect the phenotype to also be mild in mice.
* Expected scientific benefit: ANK3 is the gene that is most robustly associated with bipolar disorder in genome-wide association studies and has the highest odds ratio. We have demonstrated that this association is highly likely to be driven by this specific isoform. Determining the function of this isoform has the potential to significantly advance our understanding the disorder's etiology.
* Mouse C57BL/6. The mice will be used for organ harvesting and will not be subject to experimentation.
* 3R:
- replacement: the ANK3 protein is a scaffolding adapter protein with many interaction partners, the in vivo context is thus essential to determining its function.
- reduction: we will not sacrifice more animals than strictly necessary for our organ harvesting purposes.
- refinement: the phenotype of this KO is expected to be mild and the animals will not undergo procedures other than routine blood sampling.