U01.01.007 Mutations in DNA

Understanding the types and impacts of DNA mutations is crucial for medical students preparing for the USMLE Step 1. This guide breaks down the severity and types of mutations, providing clear examples and explanations.

Severity of DNA Damage

Severity Level	Description
Silent	Least severe, no change in protein function
Missense	Most severe, alters the reading frame downstream
Nonsense	Severe, introduces a stop codon
Frameshift	Most severe, alters reading frame downstream

Types of Single Nucleotide (Point) Mutations

Mutation Type	Description	Example
Transition	Purine to purine (e.g., A to G) or pyrimidine to pyrimidine (e.g., C to T)	–
Transversion	Purine to pyrimidine (e.g., A to T) or pyrimidine to purine (e.g., C to G)	–

Single Nucleotide Substitutions

Mutation Type	Description	Example
Silent Mutation	Nucleotide substitution codes for the same (synonymous) amino acid; often base change in the 3rd position of codon (tRNA wobble)	–
Missense Mutation	Nucleotide substitution results in a changed amino acid (conservative if the new amino acid has a similar chemical structure)	Sickle cell disease (substitution of glutamic acid with valine)
Nonsense Mutation	Nucleotide substitution results in an early stop codon (UGA, UAA, UAG). Usually results in a nonfunctional protein	–

Other Types of Mutations

Mutation Type	Description	Examples
Frameshift Mutation	Deletion or insertion of nucleotides not divisible by 3, misreading of all downstream nucleotides. Protein may be shorter or longer, and function may be disrupted or altered	Duchenne muscular dystrophy, Tay-Sachs disease
Splice Site Mutation	Retained intron in mRNA results in a protein with impaired or altered function	Rare causes of cancers, dementia, epilepsy, some types of β-thalassemia, Gaucher disease, Marfan syndrome

Points to Remember

Transition vs. Transversion:
- Transition mutations are purine-to-purine or pyrimidine-to-pyrimidine changes.
- Transversion mutations are purine-to-pyrimidine or pyrimidine-to-purine changes.
Missense Mutation Example:
- Sickle cell disease is a classic example where a single nucleotide change results in a different amino acid, altering the protein function.
Nonsense Mutations:
- These create premature stop codons, truncating the protein.
Frameshift Mutations:
- These can drastically alter the reading frame, leading to significant changes in the protein structure and function.
Splice Site Mutations:
- These affect the normal splicing of mRNA, often resulting in nonfunctional proteins.

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