M03.04.02 Genetic Mutations

A mutation refers to any permanent, heritable change in the DNA base sequence of an organism. This altered DNA sequence can affect the base sequence of mRNA and may lead to changes in the amino acid sequence of a protein. Mutations can result in genetic diseases and impact various cellular properties, including enzyme activity, nutritional requirements, antibiotic susceptibility, and morphology.

Types of Mutations

Mutations can be categorized based on their nature and effects on protein structure. A very common type is the point mutation, which can be further divided into two subtypes:

Point Mutations

• Transition: A point mutation that substitutes one purine for another purine or one pyrimidine for another pyrimidine (e.g., A-T to G-C).
• Transversion: A point mutation that replaces a purine with a pyrimidine or vice versa (e.g., A-T to T-A or C-G).

Effects on Protein Structure

Mutations can also be classified according to their effects on the protein produced by the gene. The impact of different mutation types is summarized in Table 1.

Mechanisms of Mutation

Large Segment Deletions

Large segments of DNA may be deleted from a chromosome during an unequal crossover in meiosis. Crossover events typically exchange equivalent segments between homologous chromosomes. However, unequal crossover can lead to the loss of genetic information from one homolog.

Examples:

• α-thalassemia: Caused by deletion of one or more α-globin genes from chromosome 16 due to unequal crossover.
• Cri-du-chat Syndrome: Results from a terminal deletion on the short arm of chromosome 5, leading to developmental issues.

Mutations in Splice Sites

Mutations in splice sites can significantly impact the accuracy of intron removal during mRNA processing. If a splice site is altered, spliceosomes may:

• Delete nucleotides from adjacent exons.
• Retain intron nucleotides in the final mRNA.
• Utilize an alternative splice site, potentially deleting an entire exon.

Associated Diseases:

• β-thalassemia
• Gaucher disease
• Tay-Sachs disease

Case Study: β-Thalassemia

β-thalassemia is characterized by a deficiency of β-globin protein, leading to an imbalance with α-globin levels. Various mutations, including splice site mutations, can cause this condition. An example case involves a 9-month-old infant presenting with severe anemia and splenomegaly.

Clinical Implications:

• Common treatments include regular blood transfusions, although iron overload can occur as a serious complication.

Trinucleotide Repeat Expansion

Certain genetic disorders are caused by the expansion of trinucleotide repeats within specific genes, which increases in number across generations, leading to more severe manifestations.

Clinical Features of Huntington Disease:

• Autosomal dominant inheritance.
• Mean age of onset: late 30s to early 40s.
• Symptoms include mood disturbances, impaired memory, chorea, and neurodegeneration.

Points to Remember

• Mutations can have diverse effects on an organism’s phenotype and contribute to various genetic diseases.
• Understanding the type of mutation and its consequences is crucial for diagnosing and treating genetic disorders.
• Monitoring repeat expansions in certain disorders can aid in predicting disease severity and onset age.

Bibliography

1. Griffiths, A. J. F., et al. (2015). An Introduction to Genetic Analysis. W.H. Freeman and Company.
2. Lander, E. S., et al. (2001). “Initial Sequencing and Analysis of the Human Genome.” Nature, 409(6822), 860-921.
3. Strachan, T., & Read, A. P. (2011). Human Molecular Genetics. Garland Science.
4. Thompson, J. F. (2015). “Genetic Mutations and Disease: The Role of Mutations in Disease Pathogenesis.” Journal of Medical Genetics, 52(6), 387-397.

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