I have found variants in a gene in which I have done in-silico analysis for and it is thought to be disease causing. If I want to study these variants more and see their effect, would it be justified to mimic them on animal model?
there seems to be lack of studies on specific variants or mutations in that gene, but there have been a lot of studies on knockout mouse models that makes it kind of known for us what would happen if the protein has a disfunction or not functioning at all.
So I am thinking, animal model and study the variants? Or to use cells and check if the gene will be dysfunctional and report it that way only ( and then explain what we think the outcome will be based on the status of our subjects who have the mutations and the published papers of the knockout mice)??
I am not sure I understood the question fully: so I am focusing on two possible scenarios.
1. You have found in a known gene new variants that you think would be pathogenic: but you have found them in normal people, which appears to be contradictory. If these variants were in heterozygotes your pathogenic prediction may be still correct, but the mutant allele is probably recessive: you may need a homozygote for the disease to manifest itself (and the homozygote may be extremely rare or lethal).
2. A classic ‘knock-out’ mouse tells you what happens when a particular gene is either deleted or otherwise completely inactivated. In principle pathogenic variants may or may not be equivalent to a knock-out (this has to do with loss versus gain of function, dosage effects, etc). In order to find out, strictly speaking you ought to do a knock-in of the mutation into the wild-type gene.
I hope some of this answers your question at least in part
Best wishes for your work
Lucio
Not all diseases rooted into gene. Sometimes it might be true that genome wide association (GWAS) did not explored or problem with study design. So, you should carry on if you have evidence. Good luck!
Hi
If I summarize your question , you mean that you found novel variants in known disease causing genes? If the clinical phenotype of patients is same as that of previous patients with other variants then it can be published and reported as allelic extension. If gene function is well documented then no need to check it on animal model. Just good insilico tools for pathogenecity checking would be ok.
Go for animal models if the gene is novel in implication of a disease and you have multiple patients with similar genetic defect.
Hope it helps
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