Gene Mutations and Pathogenesis Review

Page 1

Gene Mutations
Overview of gene mutations encountered in diagnostics and disease.

Page 2

Mutation Types (Miss Nody)

1. Missense: A single nucleotide change results in a codon that codes for a different amino acid.
2. Insertion/Deletion: Addition or removal of nucleotides, which can cause a shift in the reading frame (frameshift mutation).
3. Silent: Changes in nucleotide sequence that do not alter the amino acid sequence.
4. Splice Site: Mutations affecting the splicing of mRNA, potentially leading to abnormal protein products.
5. Nonsense: A mutation that changes a codon into a stop codon, prematurely terminating protein synthesis.
6. Dynamic: Mutations involving the expansion of repetitive DNA sequences.

Page 3 & 4

Dynamic Mutations
Dynamic mutations lead to diseases related to unstable expansions of short tandem repeats. Examples include:

• Fragile X Syndrome (FMR1, CGG, non-coding)
  • Stable Range: 6-54 repeats
  • Unstable Range: >200 repeats
• Myotonic Dystrophy (DMPK, CTG, non-coding)
  • Stable Range: 5-37 repeats
  • Unstable Range: >50 repeats
• Huntington Disease (HTT, CAG, coding)
  • Stable Range: 6-34 repeats
  • Unstable Range: >36 repeats
• Spinocerebellar Ataxia 1 (ATXN1, CAG, coding)
  • Stable Range: 6-38 repeats
  • Unstable Range: >39 repeats
    Dynamic mutations, especially those in untranslated regions (UTR) or coding sequences, often correlate with disease development.

Page 5

Huntington's Disease Pathophysiology

• Caused by CAG repeat expansion in the HTT gene, which codes for huntingtin protein.
• Detection through PCR and polyacrylamide gel electrophoresis.
• Mutated huntingtin has an expanded poly-glutamine tract leading to protein aggregation, dysfunctional neurotransmitter secretion, and cell apoptosis.
• Reference: Mattson Nature 2002

Page 6

CAG Repeats and Age of Onset
The graph indicates a relationship between CAG repeat length and age of motor onset in Huntington's disease, illustrating that increased repeat lengths correlate with earlier onset.

Page 7

Somatic Expansion
Research suggests that the propensity for somatic expansion of CAG repeats increases with age. Reference: Kacher et al, 2021.

Page 8

Anticipation in Genetic Disorders

• Fragile X Syndrome is an example where anticipation occurs:
  • Disease manifests at an earlier age or increases in severity in successive generations.
  • Clinical diagnosis often reveals milder forms in parents after identification in children.

Page 9

Pathogenesis Overview

• Mutations may cause loss or gain of function in proteins influencing phenotype.
• Gene expression typically reflects physiological needs; a single functioning gene copy might suffice.
• Loss of function mutations are generally recessive.
  • Some cases require two gene copies to avoid disease, termed haploinsufficiency.

Page 10

Gene/Protein Dosage

• Disease manifestation correlates with gene product dosage:
  • Dominant mutations may cause disease with 50% normal product.
  • Recessive mutations may manifest when product drops below 50% of normal.

Page 11

Dosage Impact on Pathogenesis

• Visual representation of gene/protein dosage illustrating pathways to disease with varying thresholds based on mutation types

Page 12

Waardenburg Syndrome

• Caused by loss of function mutations in the PAX3 gene.
• Characterized by allelic heterogeneity, where different mutations in the same gene yield the same phenotype.

Page 13

Genetic Associations in Facial Features
Associations of morphological traits with specific genes, showing complex genetic influences on normal populations.

Page 14

Gain of Function Mutations

• Less common than loss of function in monogenic diseases but prevalent in conditions such as tumors.
• Gain of function can involve:
  • Overexpression of genes
  • Acquisition of new functions
  • Chimeric genes affecting signaling.

Page 15

Gain of Function Examples

• PMP22 (CMT1A) - Overexpression leading to neuropathy
• GNAS (Albright syndrome) - Receptor activation
• SCN4A (Hypokalemic periodic paralysis) - Channel activity
• BCR-ABL (CML) - Fusion gene activity

Page 16

Oncogenes and Chromosomal Rearrangements

• Example: BCR-ABL1 fusion in chronic myeloid leukemia, resulting from a translocation between chromosomes 9 and 22.

Page 17

Genotype to Phenotype Correlation

• Example: Sickle Cell Anemia is a missense mutation in HBB leading to protein aggregation effects on red blood cells.

Page 18

Protein Misfolding in Disease

• Evidence from Alberts et al showcasing mutations affecting connective tissue proteins and their role in disease pathologies due to misfolding.

Page 19

Collagen Type I Synthesis

• Structure: Two α1-chains, one α2-chain aligned to form a triple helix.
• Mutations in collagen or modifying proteins can lead to osteogenesis imperfecta.

Page 20

Protein Interactions and Mutations

• Loss of interaction or functional misfolding can lead to disease presentations ranging from mild to severe manifestations, depending on mutation specifics.

Page 21

Dominant Negative Effects

• Protein dimers with one inactive allele can express dominant negative activities leading to severe phenotypes.

Page 22

Osteogenesis Imperfecta Correlation

• Genotype/phenotype correlation based on the type of mutation in collagen genes, leading to varying degrees of bone fragility.

Page 23

Genetic Disease Mechanisms Overview

• Monogenic: One gene impacts expression.
• Polygenic: Multiple genetic factors at play.
• Multifactorial: Interaction of genes with environmental influences.

Page 24

Multifactorial Disease Influences

• Understanding the combination of genetic and environmental factors contributing to disease severity and manifestation.

Page 25

Final Learning Summary

• Key takeaways about mutation impacts, disease mechanisms, protein aggregation, genotype/phenotype correlations, and multifactorial influences on health.