Dock8 Q1864E Mutation in Rodent Models for Type 1 Diabetes
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Solution Overview
Problem
Current models for studying type 1 diabetes mellitus lack a reliable animal model that accurately replicates the human condition, and there is a need for a method to analyze genetic predisposition and compound activity effectively.
Innovation Solution
Genetically manipulate rodents to introduce a mutation in the Dock8 gene, specifically a Q1864E mutation in rats and Q1865E mutation in mice, which predisposes them to insulin-dependent diabetes mellitus, combined with an MHC haplotype and a mutation in the von Willebrand factor Vwa2, to create a model for research and analysis of type 1 diabetes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If spontaneous insulin-dependent diabetes mellitus rat strain LEW.1AR1/Ztm-iddm is used as an animal model, then the model exhibits MHC haplotype RT1.A a predisposition towards type 1 diabetes mellitus, but the model lacks a identified causative mutation and has incomplete penetrance of about 60%
Solution Approach 1:
The patent creates a copy of the spontaneous LEW.1AR1/Ztm-iddm rat model by introducing the identified causative mutation (Q1864E in Dock8 gene) through targeted genetic manipulation. This allows replication of the disease phenotype with known genetic basis, improving reliability while maintaining the original model's characteristics.
Solution Approach 2:
The patent changes the genetic parameter by introducing a specific point mutation (C to G transition at position 181980 of Dock8 encoding sequence) that causes amino acid substitution (Q1864E). This parameter change transforms the spontaneous model into one with defined causative mutation, enabling more precise studies.
2Manufacturing precision
If genetic manipulation is performed to introduce the causative mutation in Dock8 gene, then the model accurately replicates human type 1 diabetes, but the process requires complex genetic manipulation including identification of candidate gene regions and SNP analysis
Solution Approach 1:
The patent performs preliminary actions by first identifying the causative mutation through linkage analysis and SNP screening of candidate gene regions. This preliminary identification simplifies subsequent genetic manipulation, as the exact target (Q1864E mutation in Dock8) is already known, making the model generation process more straightforward.
Solution Approach 2:
The patent replaces complex mechanical/genetic manipulation processes with a defined molecular approach. By identifying the specific nucleotide change (C to G at position 181980) and amino acid substitution (Q1864E), the complex process of creating an accurate disease model is simplified to introducing a known point mutation through targeted genetic techniques.
3Adaptability or versatility
If the mutation in Dock8 gene is introduced to create an accurate type 1 diabetes model, then the model allows for compound screening and genetic predisposition analysis, but the incomplete penetrance of 60% limits the consistency of the phenotype
Solution Approach 1:
The patent introduces MHC predisposition as an intermediary factor that works in combination with the Dock8 mutation to produce the diabetes phenotype. This intermediary element helps explain the incomplete penetrance, as the interaction between Dock8 mutation and MHC background influences whether the phenotype is expressed, allowing for more nuanced research into genetic predisposition.
Solution Approach 2:
The patent changes the genetic parameters by combining the Dock8 mutation (Q1864E) with specific MHC haplotype predisposition. This parameter combination approach allows researchers to study the interaction between different genetic factors, improving the model's versatility for investigating genetic predisposition while accounting for the observed 60% penetrance through defined genetic parameters.
Data Source
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AI summary
The invention relates to a mutation in the Dock8 encoding gene that is causative for type 1 diabetes mellitus at least in the rat (rattus norvegicus) or mouse, the rat or mouse preferably having an MHC predisposing towards type 1 diabetes mellitus and/or a mutation in the von Willebrand factor Vwa2. Embodiments of the invention comprise a process for generating a non-human mammal by genetic manipulation to contain at least heterozygously, preferably homozygously, the mutation causative for type 1 diabetes mellitus, preferably in combination with an MHC predisposing for type 1 diabetes mellitus and/or with a mutation in the von Willebrand factor Vwa2.