Applications of Point Mutation Models
Disease Variant Modeling
Human genetic studies identify disease associated variants, but understanding how these variants cause disease requires functional models:
Point mutation knockin provides definitive evidence linking specific variants to phenotypic outcomes.
Protein Function Studies
Point mutations enable precise dissection of protein function:
Drug Target Modeling
Point mutation models support therapeutic development:
Types of Point Mutations
Missense Mutations
Single nucleotide changes that alter the encoded amino acid:
- Most common type of disease associated coding variant
- May affect protein folding, stability, or function
- Phenotypic severity varies from silent to lethal
Nonsense Mutations
Single nucleotide changes that create premature stop codons:
- Typically result in truncated, non functional proteins
- May trigger nonsense mediated decay
- Model loss of function alleles
Silent Mutations
Nucleotide changes that do not alter the encoded amino acid:
- Create restriction sites for genotyping
- Serve as linked markers for allele tracking
- Control for targeting procedure effects
Regulatory Mutations
Changes in non coding regulatory sequences:
- Promoter or enhancer variants affecting expression level
- Splice site variants affecting transcript processing
- UTR variants affecting mRNA stability or translation
Common Point Mutation Applications
Phosphorylation Site Mutations
| Mutation Type | Effect | Application |
|---|---|---|
| Serine to Alanine (S→A) | Blocks phosphorylation | Loss of phospho regulation |
| Threonine to Alanine (T→A) | Blocks phosphorylation | Loss of phospho regulation |
| Tyrosine to Phenylalanine (Y→F) | Blocks phosphorylation | Loss of phospho regulation |
| Serine to Aspartate (S→D) | Mimics phosphorylation | Constitutive activation |
| Serine to Glutamate (S→E) | Mimics phosphorylation | Constitutive activation |
Common Disease Mutations
| Gene | Mutation | Disease | Application |
|---|---|---|---|
| APP | Swedish (K670N/M671L) | Alzheimer disease | Amyloid pathology |
| KRAS | G12D, G12V, G12C | Cancer | Oncogenic signaling |
| BRAF | V600E | Melanoma | Targeted therapy studies |
| SOD1 | G93A | ALS | Motor neuron disease |
| CFTR | F508del | Cystic fibrosis | Protein folding |
Technical Approach
Allele Design Options
Point mutation alleles can be designed with varying complexity:
Simple knockin
Point mutation only
Conditional point mutation
LoxP flanked wildtype exon enables Cre mediated conversion to mutant
Inducible point mutation
Combine with inducible Cre for temporal control
Dual reporter
Fluorescent markers distinguish wildtype from mutant expressing cells
Experimental Considerations
Homozygous vs Heterozygous Analysis
Consider the genetics of your disease or question:
Strain Background
Strain background can modify point mutation phenotypes:
Controls
Appropriate controls for point mutation studies:
Selected Publications
Point mutation models generated by ingenious targeting laboratory:
Navarro HI, Daly AE, Rodriguez B, Wu S, Ngo KA, Fraser A, Schiffman A, Liu Y, Smale ST, Chia JJ, Hoffmann A. (2025).
NF-κB RelB suppresses the inflammatory gene expression programs of dendritic cells by competing with RelA for binding to target gene promoters ↗Cell Discov 11(1): 13
Mohassel P, Hearn H, Rooney J, Zou Y, Johnson K, Norato G, Nalls MA, Yun P, Ogata T, Silverstein S, Sleboda DA, Roberts TJ, Rifkin DB, Bönnemann CG. (2025).
Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice ↗J Clin Invest 9(135): e173354
Hockemeyer K, Sakellaropoulos T, Chen X, Ivashkiv O, Sirenko M, Zhou H, Gambi G, Battistello E, Avrampou K, Sun Z, Guillamot M, Chiriboga L, Jour G, Dolgalev I, Corrigan, K, Bhatt, Osman I, Tsirigos A, Kourtis N, Aifantis I. (2024).
The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity ↗Nat Cell Bio 26(10): 1734-1744
What Researchers Say
“The people at InGenious are friendly, professional, and extremely good at what they do. I have made 5 Knockin mice with them and everything has gone like clockwork.”
— David B. Roth, MD, PhD
Perelman School of Medicine, University of Pennsylvania
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