21 - Clinical Correlations

How would these 2 factors cause skin cancer in a 60 year old construction worker?

1. Old age

2. UV exposure

1. Aging → DNA repair declines, immune surveillance weakens, and mutations accumulate.

2. UV exposure → Causes thymine dimers

What are thymine dimers, and how can they lead to cancer?

Thymine dimers are 2 adjacent thymine bases bonded abnormally, distorting DNA and blocking replication. If not fixed by nucleotide excision repair, a mutation could happen in replication. Multiple mutations of key genes could then lead to cancer

What is pallor, how is it different from anemia, and how can we check for anemia?

Pallor is paleness caused by anemia, which is a condition caused by low RBCs or hemoglobin. One of the best methods to check for anemia is to pull the eyelid down; if it is pale, not pink/red, then the patient may have anemia.

Explain how these can cause anemia:

• Iron deficiency

• Folate(Vitamin B9) + Vitamin B12 deficiency

• Chronic alcohol consumption

• Iron makes hemoglobin, the protein that carries oxygen in RBCs, so low iron = smaller RBCs w less hemoglobin

• Lack of folate and vitamin B12 will slow DNA synthesis and cell division in RBC precursors without slowing hemoglobin production, so it leads to large but immature RBCs

• Alcohol damages the bone marrow, a RBC producer

What is a neutrophil, and why does Vitamin B12/Folate deficiency cause hypersegmentation?

• Neutrophils are WBCs that fight infections and normally have 3-5 lobes.

• B12/Folate deficiency delays DNA synthesis, slowing cell division.

• While "waiting" to divide, the nucleus continues segmenting, leading to hypersegmented neutrophils (≥6 lobes).

Why does a 15-month-old child drinking only condensed milk develop leg pain and bleeding gums?

• Scurvy (Vitamin C/Ascorbic acid deficiency) weakens collagen as post-translational modification uses hydroxylation of proline/lysine which requires vitamin C, leading to fragile bones, blood vessels, and connective tissues.

• Leg pain: Due to subperiosteal hemorrhages and weakened bone structure.

• Bleeding gums: Due to fragile capillaries and poor connective tissue support.

• Cause: Condensed milk lacks Vitamin C; no fresh fruits/vegetables in the diet.

What is a COL1A1, and how does a mutation cause Osteogenesis Imperfecta (OI)[Define OI too]?

• COL1A1 encodes the α1 chain of Type I collagen(the most common collagen type), essential for bone strength

• OI, or brittle bone disease, is a genetic disorder caused by defective Type I collagen

• COL1A1 mutations (glycine substitution, nonsense mutation) disrupt collagen structure or production.

How does a glycine substitution in COL1A1 affect collagen, and why do size, charge, and polarity matter?

• Glycine is required every 3rd residue in collagen for tight packing.

• Size: Larger R groups (e.g., Valine) cause steric hindrance → severe disruption.

• Charge: Charged R groups (Asp, Arg) cause electrostatic repulsion → moderate to severe effects.

• Polarity: Polar groups (Ser, Cys) disrupt hydrogen bonding → mild to moderate disruption.

How do these glycine substitutions in COL1A1 mutation affect stability?

1. Alanine

2. Serine

3. Aspartic acid

4. Valine

• Alanine (Ala, -CH₃) → Mild OI

  • Smallest substitution after Glycine → Minimal steric hindrance.

  • Non-polar, neutral charge → Least disruption to collagen.

• Serine (Ser, -CH₂OH) → Moderate OI

  • Small-Medium size → Some steric interference.

  • Polar but uncharged → Disrupts hydrogen bonding but not as severe as charged AAs.

• Aspartic Acid (Asp, -CH₂COO⁻) → Severe OI

  • Medium-Large size → Prevents tight collagen packing.

  • Negatively charged (-1) → Causes electrostatic repulsion, destabilizing collagen.

  • Highly polar → Strongly interferes with interactions in the triple helix.

• Valine (Val, -CH(CH₃)₂) → Most lethal

  • Bulky, branched R group → Maximum steric hindrance, preventing collagen from forming properly.

  • Non-polar, neutral charge → No charge disruption, but severe physical obstruction.