Transgenic Animal Model for Rubinstein-Taybi Syndrome via CREBBP Mutation
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Solution Overview
Problem
Current models for Rubinstein-Taybi syndrome, such as mice with a wide region of the CREBBP gene artificially knocked out, do not accurately reflect natural mutations and lack a clear causative site, making them inadequate for understanding the disease's mechanisms and developing treatments.
Innovation Solution
A transgenic animal with a specific single nucleotide deletion in the CREBBP gene is created, exhibiting symptoms of Rubinstein-Taybi syndrome, and a method is developed to introduce this mutation into non-human animals, allowing for the use of these animals as models for the disease and advanced sleep phase syndrome.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a wide region of the CREBBP gene is artificially knocked out to create a model animal, then the animal exhibits symptoms of Rubinstein-Taybi syndrome, but the causative site cannot be identified and the model does not reflect natural mutations
Solution Approach 1:
The patent applies local quality by introducing a specific point mutation (c.1126G>C) at the precise causative site in the CREBBP gene, rather than knocking out a wide region. This localized approach preserves the integrity of the gene while accurately replicating the natural mutation that causes Rubinstein-Taybi syndrome, thereby identifying the exact causative site and improving disease model accuracy.
2Ease of manufacture
If a wide region of the CREBBP gene is knocked out, then a model animal is produced, but it is not known whether the model reflects a mutation that occurs in nature
Solution Approach 1:
The patent applies parameter changes by precisely altering a single nucleotide (c.1126G>C) in the CREBBP gene to match the natural mutation found in Rubinstein-Taybi syndrome patients. This specific parameter change (point mutation) maintains the ease of model production through targeted gene editing while ensuring the mutation authentically reflects what occurs in nature, thereby resolving the contradiction between manufacturing ease and measurement precision.
Data Source
AI summary
The disclosure provides a non-human transgenic animal having at least one CREBBP gene locus into which a mutation has been introduced, wherein the mutated CREBBP gene encodes a mutant CREBBP consisting of an amino acid sequence having at least 90% identity with the amino acid sequence of SEQ ID NO: 5. The disclosure also provides a method of producing the transgenic animal comprising introducing a mutation into at least one CREBBP gene locus of a non-human animal. The disclosure further provides use of the transgenic animal as a model of Rubinstein-Taybi syndrome or advanced sleep phase syndrome.